瀰漫性大B細胞淋巴瘤(diffuse large B-cell lymphoma; DLBCL) 是常見的非霍奇金淋巴瘤(non-Hodgkin lymphoma; NHL)，其發生率在近幾年來有增加的趨勢。2,3,7,8-四氯二苯並對二噁英(2,3,7,8 -tetrachlorodibenzo-p-dioxin; TCDD)為一致癌性持久性有機化合物(persistent organic compounds; POPs)，可經由活化芳香烴受體(aryl hydrocarbon receptor; AhR）來調節後續的基因表現，包含調控NFκB來引發的發炎反應。發炎體inflammasome如nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3)是調節發炎反應和誘導程序性細胞死亡如細胞焦亡(pyroptosis)和細胞凋亡(apoptosis)的複合物。有研究表示活化的發炎體所分泌的促發炎因子與NHL的進展有關。先前流行病學研究亦顯示罹患NHL與暴露含有TCDD的除草劑有相關性。然而，TCDD暴露是否會經由改變發炎體NLRP3調節功能，進而對於DLBCL癌化進展造成影響，目前機轉尚未清楚。
本研究為探究TCDD暴露是否與DLBCL生成和進展有關，先從ArrayExpress及GEO蒐集348個DLBCL臨床組織樣本及428個人類細胞株暴露TCDD之微陣列資料，分別以Networkanalyst進行巨量資料分析(meta-analysis)得到差異表現基因(differentially expressed genes; DEGs)及模組基因(module genes)，並以Cytoscape建構TCDD暴露可能藉由影響發炎體調節而誘發DLBCL生成與進展之潛在基因網路及調控路徑。基因網路分析結果顯示TCDD暴露可能會影響調控AhR-ATF4-AKT1-GSK3β-CTNNB1-RAC1-NFκB1-IL1-NLRP3路徑中之基因表現，其基因功能(gene ontology)涵蓋細胞週期、免疫反應和程序性細胞死亡。此外，DLBCL可分為生長中心型(germinal center B cell like; GCB)和活化型(activated B cell like; ABC)，臨床上ABC DLBCL具有化學治療免疫抗性(chemo-resistant)及預後不良等特性。因此，後續使用兩株人類瀰漫性大B細胞淋巴瘤SU-DHL-4 (GCB-like DLBC)和SU-DHL-2 (ABC-like DLBCL)細胞進行驗證。結果表示TCDD暴露增加AhR、CYP1A1和ATF4之基因表達，造成SU-DHL-4細胞和SU-DHL-2細胞在細胞週期G0/G1停滯。TCDD暴露也促使SU-DHL-4細胞中NLRP3活化，而SU-DHL-2細胞中活化情形則降低，這可能與SU-DHL-4細胞相對於SU-DHL-2細胞呈現較顯著之程序性細胞死亡程度有關。此外，SU-DHL-2細胞對於化療藥物doxorubicin (DOX)之敏感性較SU-DHL-4細胞差，並且在TCDD暴露下SU-DHL-2細胞對於DOX產生顯著抗性。TCDD暴露亦會增加SU-DHL-2細胞中PD-L1表現，對於SU-DHL-4細胞則無顯著影響，顯示TCDD暴露可能誘發SU-DHL-2細胞產生免疫脫逃反應而導致抗藥性。SU-DHL-2細胞經轉染調控路徑上游ATF4基因之siRNA後降低ATF4表現，TCDD暴露會增加SU-DHL-2細胞NLRP3表現及程序性細胞死亡，PD-L1則無明顯變化，此可提升對於DOX化療之敏感性。SU-DHL-4細胞ATF4下降時減少NLRP3表現而產生DOX化療抗性。由此可知暴露TCDD活化ATF4分別在SU-DHL-4細胞和SU-DHL-2細胞中產生促凋亡跟抗凋亡的作用。本研究發現TCDD暴露會誘發SU-DHL-2細胞中ATF4的抗凋亡作用來降低發炎體NLRP3調節的細胞程序性死亡，進而促進PD-L1表現而發生免疫逃逸的情形，使其產生化療抗性。透過降低ATF4表達可以改善SU-DHL-2細胞受到TCDD暴露所導致的免疫脫逃及抗藥性。因此，ATF4標靶抑制可能為暴露TCDD高危險群的ABC DLBCL患者提供一種新的治療概念。

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), which incident rate is increased recently. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of carcinogenic and persistent organic compounds (POPs) that can activate aryl hydrocarbon receptor (AhR) to regulate NFκB and induce inflammation responses. The inflammasome nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) is a complex for regulating the inflammatory response and inducing programmed cell death (e.g., pyroptosis and apoptosis). Pro-inflammatory cytokines secreted from activated inflammasome are associated with progression of NHL. A previous epidemiological study presented the risk of NHL is correlated with exposure to herbicide contained TCDD. However, the genotoxicological effect of TCDD exposure on progression of DLBCL underlying the regulation of NLRP3 inflammasome is not clearly known.
First of all, in order to investigate whether TCDD exposure is related to progression of DLBCL, this study collected microarray sample of 348 clinical human tissue of DLBCL and 428 human cell lines exposure to TCDD from ArrayExpress and GEO, and identified differential expression genes (DEGs) and module genes of DLBCL and TCDD using Networkanalyst. Cytoscape was applied to construct a network of module genes and its regulatory pathway potentially for TCDD-induced lymphomagenesis mediated by regulation of inflammasome. The analysis of gene network indicated that TCDD exposure could alter gene expression of the AhR-ATF4-AKT1-GSK3β-CTNNB1-RAC1-NFκB1- IL1β-NLRP3 pathway to induce progression of DLBCL, which was included in regulation of cell cycle phase transition, immune response and programmed cell death. DLBCL is classified into germinal center B-cell like (GCB) DLBCL and activated B-cell like (ABC) DLBCL. Clinically, ABC DLBCL is characterized more chemo-resistant and poor prognosis than GCB DLBCL. Therefore, this study used DLBCL SU-DHL-4 cells (GCB DLBCL) and SU-DHL-2 cells (ABC DLBCL) for further validation. Results indicated that TCDD exposure increased the gene expression of AhR, CYP1A1 and ATF4 and caused cell cycle arrest in G0/G1 phase in two DLBCL cells. The activation of NLRP3 inflammasome was induced in SU-DHL-4 cells, whereas attenuated in SU-DHL-2 cells, which might cause the extent of programmed cell death was greater in SU-DHL-4 cells than in SU-DHL-2 cells after TCDD exposure. Furthermore, SU-DHL-2 cells were less sensitivity to doxorubicin (DOX) treatment than SU-DHL-4 cells, and produced chemo-resistance under TCDD exposure. The expression of PD-L1 was increased in SU-DHL-2 cells after exposure to TCDD, while was not changed in SU-DHL-4 cells. These results indicated that TCDD exposure might induce immune escape in SU-DHL-2 cells leading to drug resistance. After transfection of ATF4 siRNA into SU-DHL-2 cells, TCDD exposure induced NLRP3 inflammasome-induced programmed cell death, and PD-L1 expression did not change significantly, which contributed to susceptibility of DOX treatment. In contrast, knockdown of ATF4 in SU-DHL-4 cells reduced NLRP3 inflammasome-induced programmed cell death and led to the resistance of DOX treatment. Thus, it was revealed that TCDD exposure might cause pro-apoptotic and anti-apoptotic effects of ATF4 in SU-DHL-4 cells and SU-DHL-2 cells, receptively. In conclusion, this study suggested that TCDD exposure induced anti-apoptotic effect of ATF4 to reduce NLRP3 inflammasome-induced cell death and promoted PD-L1-mediated immune escape in SU-DHL-2 cells, resulting in the resistance of chemotherapy, which could be improved by attenuation of ATF4. Therefore, targeting inhibition of ATF4 might provide a new therapeutic concept for ABC DLBCL patients exposed to high risk groups of TCDD.

摘要..........................................................II
Abstract..................................................... IV
Content ..................................................... VI
List of tables................................................IX
List of figures............................................... X
List of supplementary tables................................ XII
List of abbreviation....................................... XIII
Chapter 1 Introduction.........................................1
Chapter 2 Paper review.........................................3
2.1 Lymphoma ................................................. 3
2.1.1 Diffuse Large B-Cell Lymphoma (DLBCL)................... 6
2.1.2 Aberrant gene expression in GCB DLBCL and ABC DLBCL..... 8
2.2 Dioxins ................................................. 10
2.2.1 TCDD (2,3,7,8 -tetrachlorodibenzo-p-dioxin)............ 12
2.2.2 Mechanism of TCDD-induced activation of AhR ........... 13
2.2.3 Aberrant gene expression in exposure to TCDD........... 14
2.3 Inflammasome............................................. 16
2.3.1 NLRP3 inflammasome..................................... 16
2.3.2 Mechanism and localization of NLRP3 inflammasome activation................................................... 17
2.3.3 Dual roles of NLRP3 inflammasome....................... 19
2.4 Programmed cell death.................................... 21
2.4.1 Pyroptosis ............................................ 23
2.4.2 Apoptosis.............................................. 23
2.5 TCDD exposure might induce NLRP3 inflammsome for lymphomagenesis ..............................................................24
Chapter 3 Purpose of this study.............................. 26
Chapter 4 Material and Method................................ 28
4.1 Target genes identification by gene network analysis..... 28
4.1.1 Collection of microarray datasets ..................... 30
4.1.2 Processing and normalization of microarray datasets ... 33
4.1.3 Differential expression analysis and gene module extraction. ..............................................................33
4.1.4 Network construction for regulatory pathway identification ............................................................. 34
4.2 Cell biology assays ..................................... 36
4.2.1 Cell culture and exposure treatment ................... 36
4.2.2 Cell viability assay .................................. 37
4.2.3 Total RNA extraction .................................. 38
4.2.4 Reverse transcription polymerase chain reaction and quantitative real-time PCR .................................. 39
4.2.5 Immunofluorescence assay .............................. 41
4.2.6 Cytokine assay for IL1β and IL18 ...................... 42
4.2.7 Cell cycle analysis.................................... 43
4.2.8 Cell apoptosis analysis................................ 43
4.2.9 Cell pyroptosis analysis .............................. 44
4.2.10 Flow Cytometry ....................................... 44
4.2.11 Western Blot analysis ................................ 45
4.2.12 Transfection of siATF4 ............................... 46
4.2.13 Statistical analysis ................................. 48
Chapter 5 Results ........................................... 49
5.1 Identification of differentially expressed genes (DEGs) and module genes ................................................ 50
5.2 Gene ontological function for module genes of DLBCL and TCDD exposure .................................................... 53
5.3 Gene ontological network for module genes of DLBCL and TCDD exposure .................................................... 56
5.4 Gene regulatory network for module genes of DLBCL and TCDD exposure .................................................... 59
5.5 Identification of hub genes of DLBCL and TCDD exposure .. 61
5.6 Reconstruction of sub-network to explore potential pathway of TCDD-induced inflammasome response for DLBCL development ............................................................. 63
5.7 ROC curve analysis of target genes in carcinogenic pathway ............................................................. 65
5.8 Cell viability in exposure to TCDD exposure ............. 75
5.9 Gene expression of AhR and CYP1A1 ....................... 76
5.10 Cell cycle distribution in exposure to TCDD............. 78
5.11 Determination of the gene expression of target genes for TCDD-induced lymphoma progression ................................ 81
5.12 Activation of NLRP3 inflammasome in response to TCDD exposure ............................................................. 85
5.13 Localization of NLRP3 inflammasome after TCDD exposure.. 90
5.14 Expression of phosphorylation of NFκB p65 after TCDD exposure ............................................................. 92
5.15 Apoptosis in exposure to TCDD .......................... 94
5.16 Pyroptosis in exposure to TCDD ......................... 98
5.17 Expression of pro-inflammatory cytokines after TCDD exposure ............................................................ 101
5.18 Expression of PD-L1 after TCDD exposure ............... 104
5.19 Validation of TCDD-induced lymphomagensis pathway via siATF4 transfection in two DLBCL cells ............................ 106
5.20 Alteration of NLRP3 inflammasome and programmed cell death in exposure to TCDD after siATF4 transfection ................. 110
5.21 Alteration of expression of PDL1 in exposure to TCDD after siATF4 transfection......................................... 114
5.22 Determination of apoptosis in response to DOX treatment after TCDD exposure............................................... 116
Chapter 6 Discussion ....................................... 121
6.1 GO network of TCDD exposure corresponding to DLBCL development ............................................................ 124
6.2 Potential pathway of TCDD-induced lymphomagenesis of DLBCL .... .............................................................126
6.3 TCDD exposure caused cell cycle arrest of human DLBCL cells ... .............................................................129
6.4 TCDD exposure disturbed the expression of NLRP3 inflammasome and programmed cell death potentially for DLBCL development .... 131
6.5 ATF4 presented pro- and anti-apoptotic effects on DLBCL cells in response to TCDD exposure .................................. 134
6.6 Over-expression of ATF4 led to chemoresistance of DOX in the treatment of DLBCL ......................................... 139
Chapter 7 Conclusion ....................................... 146
Supplementary Table ........................................ 148
References ................................................. 154

1. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. Journal of Clinical Oncology. 2014;32(27):3059.
2. Zhang Q, Yang Z, Jia Z, Liu C, Guo C, Lu H, et al. ISL-1 is overexpressed in non-Hodgkin lymphoma and promotes lymphoma cell proliferation by forming a p-STAT3/pc-Jun/ISL-1 complex. Molecular cancer. 2014;13(1):181.
3. Chuang S-S, Chen S-W, Chang S-T, Kuo Y-T. Lymphoma in Taiwan: Review of 1347 neoplasms from a single institution according to the 2016 Revision of the World Health Organization Classification. Journal of the Formosan Medical Association. 2017;116(8):620-5.
4. Chuang S. Significant increase in the relative frequency of follicular lymphoma in Taiwan in the early 21st century. Journal of clinical pathology. 2008;61(7):879-80.
5. Cho S-F, Wu W-H, Yang Y-H, Chang C-S. Risk of second primary cancer in patients with B-cell non-Hodgkin lymphoma receiving rituximab-containing chemotherapy: a nationwide population-based study. Anticancer research. 2015;35(3):1809-14.
6. Chen B, Yang C-Y. Parity, age at first birth, and risk of death from non-Hodgkin’s lymphoma: a population-based cohort study in Taiwan. International journal of environmental research and public health. 2015;12(8):9131-40.
7. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011:blood-2011-01-293050.
8. Ko BS, Chen LJ, Huang HH, Wen YC, Liao CY, Chen HM, et al. Subtype‐specific epidemiology of lymphoid malignancies in Taiwan compared to Japan and the United States, 2002‐2012. Cancer medicine. 2018;7(11):5820-31.
9. Phadnis-Moghe AS, Crawford RB, Kaminski NE. Suppression of human B cell activation by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin involves altered regulation of B cell lymphoma-6. Toxicological Sciences. 2014;144(1):39-50.
10. Kumar JM, Deepika D, Srinithya B, Kalaichelvan P. Polychlorinated dibenzo P dioxins and furans-a review. International Journal of Current Research and Review. 2013;5(3):14.
11. Van den Berg M, Birnbaum LS, Denison M, De Vito M, Farland W, Feeley M, et al. The 2005 World Health Organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds. Toxicological sciences. 2006;93(2):223-41.
12. Pesatori AC. TCDD Exposure and Cancer Risk: Current Knowledge. Epidemiology. 2006;17(6):S84.
13. Zhao X, Zhang C, Hua M, Wang R, Zhong C, Yu J, et al. NLRP3 inflammasome activation plays a carcinogenic role through effector cytokine IL-18 in lymphoma. Oncotarget. 2017;8(65):108571.
14. Zhiyu W, Wang N, Wang Q, Peng C, Zhang J, Liu P, et al. The inflammasome: an emerging therapeutic oncotarget for cancer prevention. Oncotarget. 2016;7(31):50766.
15. Lin C, Zhang J. Inflammasomes in inflammation-induced cancer. Frontiers in immunology. 2017;8:271.
16. Floret N, Lucot E, Badot P-M, Mauny F, Viel J-F. A municipal solid waste incinerator as the single dominant point source of PCDD/Fs in an area of increased non-Hodgkin’s lymphoma incidence. Chemosphere. 2007;68(8):1419-26.
17. Kogevinas M, Becher H, Benn T, Bertazzi PA, Boffetta P, Bueno-de-Mesqurta HB, et al. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins an expanded and updated international cohort study. American journal of epidemiology. 1997;145(12):1061-75.
18. Rosenberg SA, De_Vita VT, Lawrence TS. DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology: Lippincott, Williams & Wilkins; 2015.
19. Kemp C. Terminal illness: a guide to nursing care: Lippincott Williams & Wilkins; 1999.
20. Shankland KR, Armitage JO, Hancock BW. Non-hodgkin lymphoma. The Lancet. 2012;380(9844):848-57.
21. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90.
22. Cerhan JR, Link BK, Habermann TM, Maurer MJ, Feldman AL, Syrbu SI, et al. Cohort Profile: The Lymphoma Specialized Program of Research Excellence (SPORE) Molecular Epidemiology Resource (MER) Cohort Study. International journal of epidemiology. 2017;46(6):1753-4i.
23. Abid MB, Nasim F, Anwar K, Pervez S. Diffuse large B cell lymphoma (DLBCL) in Pakistan: an emerging epidemic? Asian Pacific Journal of Cancer Prevention. 2005;6(4):531.
24. NIH NCI Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Non-Hodgkin Lymphoma: . Available from: https://seer.cancer.gov/statfacts/html/nhl.html.
25. American Cancer Society. Key Statistics for Non-Hodgkin Lymphoma. https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/key-statistics.html
26. 衛生福利部統計處. 106年衛生福利部國人死因統計. https://www.mohw.gov.tw/cp-3795-41794-1.html
27. Anderson L, Atman A, McShane C, Titmarsh G, Engels E, Koshiol J. Common infection-related conditions and risk of lymphoid malignancies in older individuals. British journal of cancer. 2014;110(11):2796.
28. Viel J-F, Floret N, Deconinck E, Focant J-F, De Pauw E, Cahn J-Y. Increased risk of non-Hodgkin lymphoma and serum organochlorine concentrations among neighbors of a municipal solid waste incinerator. Environment international. 2011;37(2):449-53.
29. Nelson NJ. Studies examine whether persistent organic agents may be responsible for rise in lymphoma rates. Journal of the National Cancer Institute. 2005;97(20):1490-1.
30. Hosnijeh FS, Portengen L, Bueno-de-Mesquita HB, Heederik D, Vermeulen R. Circulating Soluble CD27 and CD30 in Workers Exposed to 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD). Cancer Epidemiology and Prevention Biomarkers. 2013;22(12):2420-4.
31. Lenz G, Staudt LM. Aggressive lymphomas. New England Journal of Medicine. 2010;362(15):1417-29.
32. Norris D, Stone J. WHO classification of tumours of haematopoietic and lymphoid tissues. Geneva: WHO. 2008.
33. Al‐Hamadani M, Habermann TM, Cerhan JR, Macon WR, Maurer MJ, Go RS. Non‐H odgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the N ational C ancer D ata B ase from 1998 to 2011. American journal of hematology. 2015;90(9):790-5.
34. Smith A, Crouch S, Lax S, Li J, Painter D, Howell D, et al. Lymphoma incidence, survival and prevalence 2004–2014: sub-type analyses from the UK’s Haematological Malignancy Research Network. British journal of cancer. 2015;112(9):1575.
35. Laurini JA, Perry AM, Boilesen E, Diebold J, MacLennan KA, Müller-Hermelink HK, et al. Classification of non-Hodgkin lymphoma in Central and South America: a review of 1028 cases. Blood. 2012:blood-2012-07-440073.
36. Yoon SO, Suh C, Lee DH, Chi HS, Park CJ, Jang SS, et al. Distribution of lymphoid neoplasms in the Republic of Korea: analysis of 5318 cases according to the World Health Organization classification. American journal of hematology. 2010;85(10):760-4.
37. Chihara D, Ito H, Matsuda T, Shibata A, Katsumi A, Nakamura S, et al. Differences in incidence and trends of haematological malignancies in J apan and the U nited S tates. British journal of haematology. 2014;164(4):536-45.
38. Sun J, Yang Q, Lu Z, He M, Gao L, Zhu M, et al. Distribution of lymphoid neoplasms in China: analysis of 4,638 cases according to the World Health Organization classification. American journal of clinical pathology. 2012;138(3):429-34.
39. Fisher R, Shah P. Current trends in large cell lymphoma. Leukemia. 2003;17(10):1948.
40. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-82.
41. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503.
42. Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010:blood-2010-03-276246.
43. Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125(1):22-32.
44. Bohers E, Mareschal S, Bouzelfen A, Marchand V, Ruminy P, Maingonnat C, et al. Targetable activating mutations are very frequent in GCB and ABC diffuse large B‐cell lymphoma. Genes, Chromosomes and Cancer. 2014;53(2):144-53.
45. Loong F, Chan AC, Ho BC, Chau Y-P, Lee H-Y, Cheuk W, et al. Diffuse large B-cell lymphoma associated with chronic inflammation as an incidental finding and new clinical scenarios. Modern Pathology. 2010;23(4):493.
46. Takahashi K, Sivina M, Hoellenriegel J, Oki Y, Hagemeister FB, Fayad L, et al. CCL 3 and CCL 4 are biomarkers for B cell receptor pathway activation and prognostic serum markers in diffuse large B cell lymphoma. British journal of haematology. 2015;171(5):726-35.
47. Knittel G, Liedgens P, Korovkina D, Pallasch CP, Reinhardt HC. Rewired NFκB signaling as a potentially actionable feature of activated B‐cell‐like diffuse large B‐cell lymphoma. European journal of haematology. 2016;97(6):499-510.
48. Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q, et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma. Nature. 2009;459(7247):717.
49. Ge X, Lv X, Feng L, Liu X, Wang X. High expression and nuclear localization of β-catenin in diffuse large B-cell lymphoma. Molecular medicine reports. 2012;5(6):1433-7.
50. Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, et al. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood. 2005;105(5):1851-61.
51. Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim K-H, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470(7332):115.
52. Vega GG, Avilés-Salas A, Chalapud JR, Martinez-Paniagua M, Pelayo R, Mayani H, et al. P38 MAPK expression and activation predicts failure of response to CHOP in patients with Diffuse Large B-Cell Lymphoma. BMC cancer. 2015;15(1):722.
53. Snow AL, Xiao W, Stinson JR, Lu W, Chaigne-Delalande B, Zheng L, et al. Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. Journal of Experimental Medicine. 2012;209(12):2247-61.
54. Miniero R, De Felip E, Ferri F, Di Domenico A. An overview of TCDD half-life in mammals and its correlation to body weight. Chemosphere. 2001;43(4-7):839-44.
55. Karademir A. PCDD/F removal efficiencies of electrostatic precipitator and wet scrubbers in izaydas hazardous waste incinerator. Fresenius Environ Bull. 2003;12:1228-32.
56. Stanmore B, Clunies-Ross C. An empirical model for the de novo formation of PCDD/F in medical waste incinerators. Environmental science & technology. 2000;34(21):4538-44.
57. Quaß U, Fermann MW, Bröker G. Steps towards a European dioxin emission inventory. Chemosphere. 2000;40(9-11):1125-9.
58. Öberg L, Wagman N, Andersson R, Rappe C. De novo formation of PCDD/Fs in compost and sewage sludge–a status report. Organohalogen compounds. 1993;11:297-302.
59. Kjeller L-O, Rappe C. Time trends in levels, patterns, and profiles for polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in a sediment core from the Baltic proper. Environmental science & technology. 1995;29(2):346-55.
60. Chobtang J, De Boer IJ, Hoogenboom RL, Haasnoot W, Kijlstra A, Meerburg BG. The need and potential of biosensors to detect dioxins and dioxin-like polychlorinated biphenyls along the milk, eggs and meat food chain. Sensors. 2011;11(12):11692-716.
61. Consultation W. ‘Assessment of the Health Risk of Dioxins: Reevaluation of the Tolerable Daily Intake TDI. May, Geneva, Switzerland. 1998:25-9.
62. Van den Berg M, Van Birgelen A, Birnbaum L, Brower B, Carrier G, Dragan Y, et al. Consultation on assessment of the health risk of dioxins; re-evaluation of the tolerable daily intake (TDI): executive summary. Food Additives and Contaminants. 2000;17(4):223-40.
63. Schecter A, Quynh HT, Pavuk M, Päpke O, Malisch R, Constable JD. Food as a source of dioxin exposure in the residents of Bien Hoa City, Vietnam. Journal of Occupational and Environmental Medicine. 2003;45(8):781-8.
64. Fisher BE. Most unwanted. Environmental health perspectives. 1999;107(1):A18.
65. La Merrill M, Emond C, Kim MJ, Antignac J-P, Le Bizec B, Clément K, et al. Toxicological function of adipose tissue: focus on persistent organic pollutants. Environmental health perspectives. 2012;121(2):162-9.
66. World Health Organization. Dioxins and their effects on human health. https://www.mohw.gov.tw/cp-3795-41794-1.html
67. Schecter A, Birnbaum L, Ryan JJ, Constable JD. Dioxins: an overview. Environmental research. 2006;101(3):419-28.
68. Health USEPAOo, Assessment E. Health assessment document for 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds: US Environmental Protection Agency, Office of Research and Development …; 1994.
69. Pesatori AC, Consonni D, Rubagotti M, Grillo P, Bertazzi PA. Cancer incidence in the population exposed to dioxin after the" Seveso accident": twenty years of follow-up. Environmental Health. 2009;8(1):39.
70. McGregor DB, Partensky C, Wilbourn J, Rice JM. An IARC evaluation of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans as risk factors in human carcinogenesis. Environmental health perspectives. 1998;106(suppl 2):755-60.
71. Poellinger L. Mechanistic aspects the dioxin (aryl hydrocarbon) receptor. Food Additives & Contaminants. 2000;17(4):261-6.
72. Agostinis P, Garmyn M, Van Laethem A. The Aryl hydrocarbon receptor: an illuminating effector of the UVB response. Sci STKE. 2007;2007(403):pe49-pe.
73. Mandal PK. Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. Journal of Comparative Physiology B. 2005;175(4):221-30.
74. Safe S. Molecular biology of the Ah receptor and its role in carcinogenesis. Toxicology letters. 2001;120(1-3):1-7.
75. Wood SM, Gleadle JM, Pugh CW, Hankinson O, Ratcliffe PJ. The role of the aryl hydrocarbon receptor nuclear translocator (ARNT) in hypoxic induction of gene expression studies in ARNT-deficient cells. Journal of Biological Chemistry. 1996;271(25):15117-23.
76. Larsen MC, Angus WG, Brake PB, Eltom SE, Sukow KA, Jefcoate CR. Characterization of CYP1B1 and CYP1A1 expression in human mammary epithelial cells: role of the aryl hydrocarbon receptor in polycyclic aromatic hydrocarbon metabolism. Cancer Research. 1998;58(11):2366-74.
77. Mimura J, Fujii-Kuriyama Y. Functional role of AhR in the expression of toxic effects by TCDD. Biochimica et Biophysica Acta (BBA)-General Subjects. 2003;1619(3):263-8.
78. Furue M, Takahara M, Nakahara T, Uchi H. Role of AhR/ARNT system in skin homeostasis. Archives of Dermatological Research. 2014;306(9):769-79.
79. Cao SS, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxidants & redox signaling. 2014;21(3):396-413.
80. Salvado L, Palomer X, Barroso E, Vázquez-Carrera M. Targeting endoplasmic reticulum stress in insulin resistance. Trends in Endocrinology & Metabolism. 2015;26(8):438-48.
81. Chong WC, Shastri MD, Eri R. Endoplasmic reticulum stress and oxidative stress: a vicious nexus implicated in bowel disease pathophysiology. International journal of molecular sciences. 2017;18(4):771.
82. Furue M, Tsuji G, Mitoma C, Nakahara T, Chiba T, Morino-Koga S, et al. Gene regulation of filaggrin and other skin barrier proteins via aryl hydrocarbon receptor. Journal of dermatological science. 2015;80(2):83-8.
83. Zhou Y, Sun P, Wang T, Chen K, Zhu W, Wang H. Inhibition of calcium influx reduces dysfunction and apoptosis in lipotoxic pancreatic β-cells via regulation of endoplasmic reticulum stress. PLoS One. 2015;10(7):e0132411.
84. Vogel CF, Khan EM, Leung PS, Gershwin ME, Chang WL, Wu D, et al. Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-kappaB. J Biol Chem. 2014;289(3):1866-75. doi: 10.1074/jbc.M113.505578. PubMed PMID: 24302727; PubMed Central PMCID: PMCPMC3894361.
85. Wang Y, Abu-Asab M, Shen D, Chu X, Ogilvy A, Tuo J, et al. NLRP3 inflammasome activation in human retinal pigment epithelium under inflammation and oxidative stress. Investigative Ophthalmology & Visual Science. 2013;54(15):149-.
86. Jin M, Lo J, Yu H, Miao M, Wang G, Ai H, et al. Exposure to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin promotes inflammation in mouse testes: the critical role of Klotho in Sertoli cells. Toxicology letters. 2018.
87. Bekki K, Vogel H, Li W, Ito T, Sweeney C, Haarmann-Stemmann T, et al. The aryl hydrocarbon receptor (AhR) mediates resistance to apoptosis induced in breast cancer cells. Pesticide biochemistry and physiology. 2015;120:5-13.
88. Xie G, Peng Z, Raufman J-P. Src-mediated aryl hydrocarbon and epidermal growth factor receptor cross talk stimulates colon cancer cell proliferation. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2012;302(9):G1006-G15.
89. Abdelrahim M, Smith R, Safe S. Aryl hydrocarbon receptor gene silencing with small inhibitory RNA differentially modulates Ah-responsiveness in MCF-7 and HepG2 cancer cells. Molecular pharmacology. 2003;63(6):1373-81.
90. Knerr S, Schrenk D. Carcinogenicity of 2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin in experimental models. Molecular nutrition & food research. 2006;50(10):897-907.
91. Xu J, Ye Y, Huang F, Chen H, Wu H, Huang J, et al. Association between dioxin and cancer incidence and mortality: a meta-analysis. Scientific reports. 2016;6:38012.
92. Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nature Reviews Cancer. 2014;14(8):517.
93. Ozaki E, Campbell M, Doyle SL. Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives. Journal of inflammation research. 2015;8:15.
94. Lamkanfi M, Dixit VM. Inflammasomes and their roles in health and disease. Annual review of cell and developmental biology. 2012;28:137-61.
95. Shao B-Z, Xu Z-Q, Han B-Z, Su D-F, Liu C. NLRP3 inflammasome and its inhibitors: a review. Frontiers in pharmacology. 2015;6:262.
96. Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell. 2014;157(5):1013-22.
97. Franchi L, Warner N, Viani K, Nuñez G. Function of Nod‐like receptors in microbial recognition and host defense. Immunological reviews. 2009;227(1):106-28.
98. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Molecular cell. 2002;10(2):417-26.
99. Edge C. NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression Bauernfeind. Franz G.787-91.
100. Jo E-K, Kim JK, Shin D-M, Sasakawa C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cellular & molecular immunology. 2016;13(2):148.
101. Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell. 2013;153(2):348-61.
102. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221.
103. He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends in biochemical sciences. 2016;41(12):1012-21.
104. Bryan NB, Dorfleutner A, Rojanasakul Y, Stehlik C. Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain. The Journal of Immunology. 2009;182(5):3173-82.
105. Fink SL, Cookson BT. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infection and immunity. 2005;73(4):1907-16.
106. Reed JC. Dysregulation of apoptosis in cancer. Journal of clinical oncology. 1999;17(9):2941-.
107. Ungerbäck J, Belenki D, Jawad ul-Hassan A, Fredrikson M, Fransén K, Elander N, et al. Genetic variation and alterations of genes involved in NFκB/TNFAIP3-and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer. Carcinogenesis. 2012;33(11):2126-34.
108. Dupaul-Chicoine J, Arabzadeh A, Dagenais M, Douglas T, Champagne C, Morizot A, et al. The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity. 2015;43(4):751-63.
109. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature immunology. 2008;9(8):847.
110. Wei Q, Mu K, Li T, Zhang Y, Yang Z, Jia X, et al. Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression. Laboratory investigation. 2014;94(1):52.
111. Li S, Liang X, Ma L, Shen L, Li T, Zheng L, et al. MiR-22 sustains NLRP3 expression and attenuates H. pylori-induced gastric carcinogenesis. Oncogene. 2018;37(7):884.
112. He A, Shao J, Zhang Y, Lu H, Wu Z, Xu Y. CD200Fc reduces LPS-induced IL-1β activation in human cervical cancer cells by modulating TLR4-NF-κB and NLRP3 inflammasome pathway. Oncotarget. 2017;8(20):33214.
113. Wang Y, Kong H, Zeng X, Liu W, Wang Z, Yan X, et al. Activation of NLRP3 inflammasome enhances the proliferation and migration of A549 lung cancer cells. Oncology reports. 2016;35(4):2053-64.
114. Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine & growth factor reviews. 2010;21(1):11-9.
115. Jia C, Liang L, Yang L, Zhao F, Bai J. Expression levels of TWIST1 are associated with the clinicopathological stage of B‑cell non‑Hodgkin lymphoma. Experimental and therapeutic medicine. 2014;8(5):1489-93.
116. Haabeth OAW, Lorvik KB, Yagita H, Bogen B, Corthay A. Interleukin-1 is required for cancer eradication mediated by tumor-specific Th1 cells. Oncoimmunology. 2016;5(1):e1039763.
117. North R, Neubauer RH, Huang J, Newton RC, Loveless SE. Interleukin 1-induced, T cell-mediated regression of immunogenic murine tumors. Requirement for an adequate level of already acquired host concomitant immunity. Journal of Experimental Medicine. 1988;168(6):2031-43.
118. Lodish H, Darnell JE, Berk A, Kaiser CA, Krieger M, Scott MP, et al. Molecular cell biology: Macmillan; 2008.
119. Lamkanfi M, Dixit VM. Manipulation of host cell death pathways during microbial infections. Cell host & microbe. 2010;8(1):44-54.
120. Jorgensen I, Miao EA. Pyroptotic cell death defends against intracellular pathogens. Immunological reviews. 2015;265(1):130-42.
121. Fink SL, Cookson BT. Caspase‐1‐dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cellular microbiology. 2006;8(11):1812-25.
122. Yuan Y-Y, Xie K-X, Wang S-L, Yuan L-W. Inflammatory caspase-related pyroptosis: mechanism, regulation and therapeutic potential for inflammatory bowel disease. Gastroenterology report. 2018;6(3):167-76.
123. Shi J, Gao W, Shao F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends in biochemical sciences. 2017;42(4):245-54.
124. Wang Y, Yin B, Li D, Wang G, Han X, Sun X. GSDME mediates caspase-3-dependent pyroptosis in gastric cancer. Biochemical and biophysical research communications. 2018;495(1):1418-25.
125. Wang Y, Gao W, Shi X, Ding J, Liu W, He H, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547(7661):99.
126. Elmore S. Apoptosis: a review of programmed cell death. Toxicologic pathology. 2007;35(4):495-516.
127. Reed JC. Mechanisms of apoptosis. The American journal of pathology. 2000;157(5):1415-30.
128. Vogel CF, Khan EM, Leung PS, Gershwin ME, Chang WW, Wu D, et al. Cross-talk between Aryl hydrocarbon receptor and the inflammatory response a role for nuclear factor-κB. Journal of Biological Chemistry. 2014;289(3):1866-75.
129. Duan Z, Zhao J, Fan X, Tang C, Liang L, Nie X, et al. The PERK-eIF2α signaling pathway is involved in TCDD-induced ER stress in PC12 cells. Neurotoxicology. 2014;44:149-59.
130. Jiang H-Y, Wek SA, McGrath BC, Scheuner D, Kaufman RJ, Cavener DR, et al. Phosphorylation of the α subunit of eukaryotic initiation factor 2 is required for activation of NF-κB in response to diverse cellular stresses. Molecular and cellular biology. 2003;23(16):5651-63.
131. Kim S, Joe Y, Jeong SO, Zheng M, Back SH, Park SW, et al. Endoplasmic reticulum stress is sufficient for the induction of IL-1β production via activation of the NF-κB and inflammasome pathways. Innate immunity. 2014;20(8):799-815.
132. Fu XY. STAT3 in immune responses and inflammatory bowel diseases. Cell research. 2006;16(2):214.
133. Lu L, Zhu F, Zhang M, Li Y, Drennan AC, Kimpara S, et al. Gene regulation and suppression of type I interferon signaling by STAT3 in diffuse large B cell lymphoma. Proceedings of the National Academy of Sciences. 2018;115(3):E498-E505.
134. Weichand B, Popp R, Dziumbla S, Mora J, Strack E, Elwakeel E, et al. S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β. Journal of Experimental Medicine. 2017;214(9):2695-713.
135. Salaro E, Rambaldi A, Falzoni S, Amoroso FS, Franceschini A, Sarti AC, et al. Involvement of the P2X7-NLRP3 axis in leukemic cell proliferation and death. Scientific reports. 2016;6:26280.
136. Viel J-F, Arveux P, Baverel J, Cahn J-Y. Soft-tissue sarcoma and non-Hodgkin's lymphoma clusters around a municipal solid waste incinerator with high dioxin emission levels. American journal of epidemiology. 2000;152(1):13-9.
137. Karki R, Man SM, Kanneganti T-D. Inflammasomes and cancer. Cancer immunology research. 2017;5(2):94-9.
138. Xia J, Gill EE, Hancock RE. NetworkAnalyst for statistical, visual and network-based meta-analysis of gene expression data. Nature protocols. 2015;10(6):823.
139. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome research. 2003;13(11):2498-504.
140. Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, et al. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009;25(8):1091-3.
141. Bindea G, Galon J, Mlecnik B. CluePedia Cytoscape plugin: pathway insights using integrated experimental and in silico data. Bioinformatics. 2013;29(5):661-3.
142. Chin C-H, Chen S-H, Wu H-H, Ho C-W, Ko M-T, Lin C-Y. cytoHubba: identifying hub objects and sub-networks from complex interactome. Bmc Syst Biol. 2014;8(4):S11.
143. Hashwah H, Schmid CA, Kasser S, Bertram K, Stelling A, Manz MG, et al. Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth. Proceedings of the National Academy of Sciences. 2017;114(36):9701-6.
144. Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471(7337):189.
145. Steenland K, Deddens J, Piacitelli L. Risk assessment for 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) based on an epidemiologic study. American journal of epidemiology. 2001;154(5):451-8.
146. Martinon F, Chen X, Lee A-H, Glimcher LH. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nature immunology. 2010;11(5):411.
147. Boaru SG, Borkham-Kamphorst E, Van de Leur E, Lehnen E, Liedtke C, Weiskirchen R. NLRP3 inflammasome expression is driven by NF-κB in cultured hepatocytes. Biochemical and biophysical research communications. 2015;458(3):700-6.
148. Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nature medicine. 2015;21(7):677.
149. Wilson T, Johnston P, Longley D. Anti-apoptotic mechanisms of drug resistance in cancer. Current cancer drug targets. 2009;9(3):307-19.
150. Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nature Reviews Immunology. 2016;16(7):407.
151. Ma Y, Jiang J, Gao Y, Shi T, Zhu X, Zhang K, et al. Research progress of the relationship between pyroptosis and disease. American journal of translational research. 2018;10(7):2213.
152. Crusz SM, Balkwill FR. Inflammation and cancer: advances and new agents. Nature reviews Clinical oncology. 2015;12(10):584.
153. Zitvogel L, Kepp O, Galluzzi L, Kroemer G. Inflammasomes in carcinogenesis and anticancer immune responses. Nature immunology. 2012;13(4):343.
154. Dinarello CA. Overview of the IL‐1 family in innate inflammation and acquired immunity. Immunological reviews. 2018;281(1):8-27.
155. Xiang X, Yu P-C, Long D, Liao X-L, Zhang S, You X-M, et al. Prognostic value of PD–L1 expression in patients with primary solid tumors. Oncotarget. 2018;9(4):5058.
156. Chen N, Fang W, Zhan J, Hong S, Tang Y, Kang S, et al. Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. Journal of thoracic oncology. 2015;10(6):910-23.
157. Zhou TC, Sankin AI, Porcelli SA, Perlin DS, Schoenberg MP, Zang X, editors. A review of the PD-1/PD-L1 checkpoint in bladder cancer: From mediator of immune escape to target for treatment. Urologic Oncology: Seminars and Original Investigations; 2017: Elsevier.
158. Goodman A, Patel SP, Kurzrock R. PD-1–PD-L1 immune-checkpoint blockade in B-cell lymphomas. Nature reviews Clinical oncology. 2017;14(4):203.
159. Lastwika KJ, Wilson W, Li QK, Norris J, Xu H, Ghazarian SR, et al. Control of PD-L1 expression by oncogenic activation of the AKT–mTOR pathway in non–small cell lung cancer. Cancer research. 2016;76(2):227-38.
160. Wu X, Li Y, Liu X, Chen C, Harrington SM, Cao S, et al. Targeting B7-H1 (PD-L1) sensitizes cancer cells to chemotherapy. Heliyon. 2018;4(12):e01039.
161. Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. New England Journal of Medicine. 2002;346(25):1937-47.
162. Wang S, Konorev EA, Kotamraju S, Joseph J, Kalivendi S, Kalyanaraman B. Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms intermediacy of H2O2-and p53-dependent pathways. Journal of Biological Chemistry. 2004;279(24):25535-43.
163. Castro DJ, Löhr CV, Fischer KA, Pereira CB, Williams DE. Lymphoma and lung cancer in offspring born to pregnant mice dosed with dibenzo [a, l] pyrene: the importance of in utero vs. lactational exposure. Toxicology and applied pharmacology. 2008;233(3):454-8.
164. Vogel CF, Li W, Sciullo E, Newman J, Hammock B, Reader JR, et al. Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression. The American journal of pathology. 2007;171(5):1538-48.
165. Bell HS, Ryan KM. Intracellular signalling and cancer: complex pathways lead to multiple targets. European Journal of Cancer. 2005;41(2):206-15.
166. Adjei AA, Hidalgo M. Intracellular signal transduction pathway proteins as targets for cancer therapy. Journal of Clinical Oncology. 2005;23(23):5386-403.
167. Mitchell KA, Lockhart CA, Huang G, Elferink CJ. Sustained aryl hydrocarbon receptor activity attenuates liver regeneration. Molecular pharmacology. 2006;70(1):163-70.
168. Kopf P, Walker M. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin increases reactive oxygen species production in human endothelial cells via induction of cytochrome P4501A1. Toxicology and applied pharmacology. 2010;245(1):91-9.
169. Xu G, Zhou Q, Wan C, Wang Y, Liu J, Li Y, et al. 2, 3, 7, 8-TCDD induces neurotoxicity and neuronal apoptosis in the rat brain cortex and PC12 cell line through the down-regulation of the Wnt/β-catenin signaling pathway. Neurotoxicology. 2013;37:63-73.
170. Su N, Wang P, Li Y. Role of Wnt/β‑catenin pathway in inducing autophagy and apoptosis in multiple myeloma cells. Oncology letters. 2016;12(6):4623-9.
171. Kong Y, Chen G, Xu Z, Yang G, Li B, Wu X, et al. Pterostilbene induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma cells. Scientific reports. 2016;6:37417.
172. Mathur R, Sehgal L, Braun FK, Berkova Z, Romaguerra J, Wang M, et al. Targeting Wnt pathway in mantle cell lymphoma-initiating cells. Journal of hematology & oncology. 2015;8(1):63.
173. Stejskalova L, Pavek P. The function of cytochrome P450 1A1 enzyme (CYP1A1) and aryl hydrocarbon receptor (AhR) in the placenta. Current pharmaceutical biotechnology. 2011;12(5):715-30.
174. Zhou B, Wang X, Li F, Wang Y, Yang L, Zhen X, et al. Mitochondrial activity and oxidative stress functions are influenced by the activation of AhR-induced CYP1A1 overexpression in cardiomyocytes. Molecular medicine reports. 2017;16(1):174-80.
175. Jagannathan L, Jose CC, Tanwar VS, Bhattacharya S, Cuddapah S. Identification of a unique gene expression signature in mercury and 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin co-exposed cells. Toxicology research. 2017;6(3):312-23.
176. Ameri K, Harris AL. Activating transcription factor 4. The international journal of biochemistry & cell biology. 2008;40(1):14-21.
177. Hyoda K, Hosoi T, Horie N, Okuma Y, Ozawa K, Nomura Y. PI3K-Akt inactivation induced CHOP expression in endoplasmic reticulum-stressed cells. Biochemical and biophysical research communications. 2006;340(1):286-90.
178. Nusse R. Wnt signaling in disease and in development. Cell research. 2005;15(1):28.
179. Kawajiri K, Kobayashi Y, Ohtake F, Ikuta T, Matsushima Y, Mimura J, et al. Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands. Proceedings of the national academy of sciences. 2009;106(32):13481-6.
180. Procházková J, Kabátková M, Bryja V, Umannová L, Bernatík O, Kozubík A, et al. The interplay of the aryl hydrocarbon receptor and β-catenin alters both AhR-dependent transcription and Wnt/β-catenin signaling in liver progenitors. Toxicological Sciences. 2011;122(2):349-60.
181. Ma B, Hottiger MO. Crosstalk between Wnt/β-catenin and NF-κB signaling pathway during inflammation. Frontiers in immunology. 2016;7:378.
182. Naskar D, Maiti G, Chakraborty A, Roy A, Chattopadhyay D, Sen M. Wnt5a–Rac1–NF-κB homeostatic circuitry sustains innate immune functions in macrophages. The Journal of Immunology. 2014;192(9):4386-97.
183. Liu J, Liao Y, Ma K, Wang Y, Zhang G, Yang R, et al. PI3K is required for the physical interaction and functional inhibition of NF-κB by β-catenin in colorectal cancer cells. Biochemical and biophysical research communications. 2013;434(4):760-6.
184. Barhoover MA, Hall JM, Greenlee WF, Thomas RS. Aryl hydrocarbon receptor regulates cell cycle progression in human breast cancer cells via a functional interaction with cyclin-dependent kinase 4. Molecular pharmacology. 2010;77(2):195-201.
185. Shimba S, Komiyama K, Moro I, Tezuka M. Overexpression of the aryl hydrocarbon receptor (AhR) accelerates the cell proliferation of A549 cells. The Journal of Biochemistry. 2002;132(5):795-802.
186. Roos WP, Kaina B. DNA damage-induced cell death by apoptosis. Trends in molecular medicine. 2006;12(9):440-50.
187. Surget S, Khoury MP, Bourdon J-C. Uncovering the role of p53 splice variants in human malignancy: a clinical perspective. OncoTargets and therapy. 2014;7:57.
188. Miao Y, Medeiros LJ, Xu-Monette ZY, YOUNG KH. Dysregulation of cell survival in diffuse large B cell lymphoma: mechanisms and therapeutic targets. Frontiers in Oncology. 2019;9:107.
189. Kaufmann W, Kaufman D. Cell cycle control, DNA repair and initiation of carcinogenesis. The FASEB journal. 1993;7(12):1188-91.
190. Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 1998;92(6):725-34.
191. Jia Y, Zhang C, Hua M, Wang M, Chen P, Ma D. Aberrant NLRP3 inflammasome associated with aryl hydrocarbon receptor potentially contributes to the imbalance of T‑helper cells in patients with acute myeloid leukemia. Oncology letters. 2017;14(6):7031-44.
192. Allen IC, TeKippe EM, Woodford R-MT, Uronis JM, Holl EK, Rogers AB, et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. Journal of Experimental Medicine. 2010;207(5):1045-56.
193. Hu B, Elinav E, Flavell RA. Inflammasome-mediated suppression of inflammation-induced colorectal cancer progression is mediated by direct regulation of epithelial cell proliferation. Cell Cycle. 2011;10(12):1936-9.
194. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nature medicine. 2009;15(10):1170.
195. Huber S, Gagliani N, Zenewicz LA, Huber FJ, Bosurgi L, Hu B, et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature. 2012;491(7423):259.
196. Senju H, Kumagai A, Nakamura Y, Yamaguchi H, Nakatomi K, Fukami S, et al. Effect of IL-18 on the Expansion and Phenotype of Human Natural Killer Cells: Application to Cancer Immunotherapy. International journal of biological sciences. 2018;14(3):331.
197. Wang C, Guo F. Effects of activating transcription factor 4 deficiency on carbohydrate and lipid metabolism in mammals. IUBMB life. 2012;64(3):226-30.
198. Rozpedek W, Pytel D, Mucha B, Leszczynska H, Diehl JA, Majsterek I. The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Current molecular medicine. 2016;16(6):533-44.
199. Wang W-A, Groenendyk J, Michalak M. Endoplasmic reticulum stress associated responses in cancer. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2014;1843(10):2143-9.
200. Wortel IM, van der Meer LT, Kilberg MS, van Leeuwen FN. Surviving stress: modulation of ATF4-mediated stress responses in normal and malignant cells. Trends in Endocrinology & Metabolism. 2017;28(11):794-806.
201. Zhang C, Bai N, Chang A, Zhang Z, Yin J, Shen W, et al. ATF4 is directly recruited by TLR4 signaling and positively regulates TLR4-trigged cytokine production in human monocytes. Cellular & molecular immunology. 2013;10(1):84.
202. D’Osualdo A, Anania VG, Yu K, Lill JR, Kaufman RJ, Matsuzawa S-i, et al. Transcription factor ATF4 induces NLRP1 inflammasome expression during endoplasmic reticulum stress. PLoS One. 2015;10(6):e0130635.
203. Gan L, Liu Z, Luo D, Ren Q, Wu H, Li C, et al. Reduced endoplasmic reticulum stress-mediated autophagy is required for leptin alleviating inflammation in adipose tissue. Frontiers in immunology. 2017;8:1507.
204. Han CY, Rho HS, Kim A, Kim TH, Jang K, Jun DW, et al. FXR inhibits endoplasmic reticulum stress-induced NLRP3 inflammasome in hepatocytes and ameliorates liver injury. Cell reports. 2018;24(11):2985-99.
205. Martín-Pérez R, Palacios C, Yerbes R, Cano-González A, Iglesias-Serret D, Gil J, et al. Activated ERBB2/HER2 licenses sensitivity to apoptosis upon endoplasmic reticulum stress through a PERK-dependent pathway. Cancer research. 2014;74(6):1766-77.
206. Ramírez-Peinado S, Alcázar-Limones F, Lagares-Tena L, El Mjiyad N, Caro-Maldonado A, Tirado OM, et al. 2-deoxyglucose induces Noxa-dependent apoptosis in alveolar rhabdomyosarcoma. Cancer research. 2011;71(21):6796-806.
207. Zeng H, Zhang J-m, Du Y, Wang J, Ren Y, Li M, et al. Crosstalk between ATF4 and MTA1/HDAC1 promotes osteosarcoma progression. Oncotarget. 2016;7(6):7329.
208. Nagelkerke A, Bussink J, Mujcic H, Wouters BG, Lehmann S, Sweep FC, et al. Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response. Breast Cancer Research. 2013;15(1):R2.
209. Dey S, Tameire F, Koumenis C. PERK-ing up autophagy during MYC-induced tumorigenesis. Autophagy. 2013;9(4):612-4.
210. Ding W-X, Ni H-M, Gao W, Hou Y-F, Melan MA, Chen X, et al. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. Journal of Biological Chemistry. 2007;282(7):4702-10.
211. Namba T, Chu K, Kodama R, Byun S, Yoon KW, Hiraki M, et al. Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway. Oncotarget. 2015;6(24):19990.
212. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity. 2004;20(3):337-47.
213. Stovgaard ES, Dyhl-Polk A, Roslind A, Balslev E, Nielsen D. PD-L1 expression in breast cancer: expression in subtypes and prognostic significance: a systematic review. Breast cancer research and treatment. 2019;174(3):571-84.
214. Wang G-Z, Zhang L, Zhao X-C, Gao S-H, Qu L-W, Yu H, et al. The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy. Nature communications. 2019;10(1):1125.
215. Song M-K, Park B-B, Uhm J. Understanding Immune Evasion and Therapeutic Targeting Associated with PD-1/PD-L1 Pathway in Diffuse Large B-cell Lymphoma. International journal of molecular sciences. 2019;20(6):1326.
216. Kiyasu J, Miyoshi H, Hirata A, Arakawa F, Ichikawa A, Niino D, et al. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood. 2015;126(19):2193-201.
217. Bazhin A, von Ahn K, Fritz J, Werner J, Karakhanova S. Interferon-α up-regulates the expression of PD-L1 molecules on immune cells through STAT3 and p38 signaling. Frontiers in immunology. 2018;9:2129.
218. Chang L-C, Chen T-P, Kuo W-K, Hua C-C. The Protein Expression of PDL1 Is Highly Correlated with Those of eIF2α and ATF4 in Lung Cancer. Disease markers. 2018;2018.
219. Terawaki S, Chikuma S, Shibayama S, Hayashi T, Yoshida T, Okazaki T, et al. IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. The Journal of Immunology. 2011;186(5):2772-9.
220. Jiang Q, Li F, Shi K, Wu P, An J, Yang Y, et al. ATF4 activation by the p38MAPK–eIF4E axis mediates apoptosis and autophagy induced by selenite in Jurkat cells. FEBS letters. 2013;587(15):2420-9.
221. Zong Y, Feng S, Yu C, Cheng J, Lu G. Up-regulated ATF4 expression increases cell sensitivity to apoptosis in response to radiation. Cellular Physiology and Biochemistry. 2017;41(2):784-94.
222. Armstrong JL, Flockhart R, Veal GJ, Lovat PE, Redfern CP. Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. Journal of Biological Chemistry. 2010;285(9):6091-100.
223. Shringarpure R, Catley L, Bhole D, Burger R, Podar K, Tai YT, et al. Gene expression analysis of B‐lymphoma cells resistant and sensitive to bortezomib. British journal of haematology. 2006;134(2):145-56.
224. Milani M, Rzymski T, Mellor HR, Pike L, Bottini A, Generali D, et al. The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib. Cancer research. 2009;69(10):4415-23.
225. Igarashi T, Izumi H, Uchiumi T, Nishio K, Arao T, Tanabe M, et al. Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines. Oncogene. 2007;26(33):4749.
226. Hu J, Dang N, Menu E, De Bryune E, Xu D, Van Camp B, et al. Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition. Blood. 2012;119(3):826-37.
227. Moeckel S, LaFrance K, Wetsch J, Seliger C, Riemenschneider MJ, Proescholdt M, et al. ATF4 contributes to autophagy and survival in sunitinib treated brain tumor initiating cells (BTICs). Oncotarget. 2019;10(3):368.
228. Ritprajak P, Azuma M. Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma. Oral oncology. 2015;51(3):221-8.
229. Noh H, Hu J, Wang X, Xia X, Satelli A, Li S. Immune checkpoint regulator PD-L1 expression on tumor cells by contacting CD11b positive bone marrow derived stromal cells. Cell Communication and Signaling. 2015;13(1):14.
230. Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM. Programmed death ligand 1 is expressed by non–Hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clinical cancer research. 2011;17(13):4232-44.