嗎啡是一種鴉片類止痛藥，然而卻有濫用甚至當作毒品使用的情況，可能導致人的依賴性和成癮的現象，而有些研究指出長期使用嗎啡會促進腫瘤血管新生和癌症進展。目前仍不清楚嗎啡成癮對腫瘤發生的分子機制，我們先前已建立嗎啡成癮的C57BL/6小鼠乳腺腫瘤模型，並發現相較於給予生理食鹽水的小鼠，源自EO771 (三陰性乳癌細胞株) 的腫瘤體積和重量明顯增加，此外我們觀察到嗎啡成癮的C57BL/6小鼠的肺轉移發生率更高。為了更進一步了解嗎啡對於腫瘤生長和轉移的影響，將RNA定序 (RNA-sequencing) 結果分析嗎啡成癮組與生理食鹽水組的腫瘤中基因圖譜表現的差異。接著使用KEGG (Kyoto Encyclopedia of Genes and Genomes) 和GO-term (Gene Ontology) 分析差異表現的基因之分子功能與生物路徑，根據分析結果，嗎啡成癮組中表現量增加的基因參與了癌症的信號路徑，包括PPAR、AMPK、cGMP-PKG 訊息傳遞路徑，這些路徑參與粒線體生物合成，其中OPRD1、ADRA1、PDE3A、MMP1基因正向調控乳癌細胞增生和轉移。PGC-1α是粒線體生物合成、氧化磷酸化和脂肪酸代謝的主要調節因子。我們研究顯示，嗎啡成癮組中PGC-1α表現低於生理食鹽水組，這可能與乳癌進展相關。

Morphine is an opioid analgesic drug. However, it is abused or even used as a drug, which may lead to dependence and addiction. Several studies have reported that long term use of morphine promotes angiogenesis and cancer progression. The underlying molecular mechanism of morphine addition-mediated tumor progression remain unclear. We previously had established morphine-addicted C57BL/6 breast tumor model, and found increased volume and weight of EO771 (a triple negative breast cancer cell line)-derived tumor xenografts compared to mice treated with saline. Furthermore, we observed a higher incidence rate of lung metastasis in morphine-addicted C57BL/6 mice. In order to understand the effect of morphine on tumor growth and metastasis, the RNA-sequencing (RNA-seq) profiles of tumors isolated from morphine-addicted or saline-treated mice was compared. KEGG and GO analysis were used to identify molecular function and pathways among the differentially expressed genes. According to the results, most up-regulated genes were involved in cancer signaling-related pathways including peroxisome proliferator-activated receptor, AMP-activated protein kinase, and cyclic guanosine monophosphate-protein kinase G signaling pathways, which were related to mediate mitochondrial biogenesis. OPRD1, ADRA1, PDE3A and MMP1 positively regulate the proliferation and metastasis of breast cancer cells. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is master regulator of mitochondrial biogenesis, oxidative phosphorylation, and fatty acid metabolism through interacting with several transcription factors. Our analysis indicates that the PGC-1α expression in morphine-addicted groups is lower than that in saline groups, suggesting that lower level of PGC-1α expression may be associated with breast cancer progression.

摘要…………………………………………………………………………………………………………………………I
Abstract…………………………………………………………………………………………………………………II
致謝………………………………………………………………………………………………………………………III
目錄………………………………………………………………………………………………………………………VI
介紹…………………………………………………………………………………………………………………………1
1. 乳癌 (Breast cancer)…………………………………………………………………………………………1
1.1 乳癌的發生與進程 (Breast cancer development and rogression)……………………1
1.2 乳癌的轉移 (Metastasis of breast cancer)…………………………………………………………2
1.3 癌症的代謝 (Cancer metabolism)……………………………………………………………………3
1.4 腫瘤微環境 (Tumor microenvironment)……………………………………………………………7
1.5 乳癌的治療 (Therapies for breast cancer)…………………………………………………………8
2. 嗎啡 (Morphine) 對癌症的作用………………………………………………………………………9
3. 表觀遺傳 (Epigenetic) 調控機制影響基因表現………………………………………………10
材料與方法…………………………………………………………………………………………………………….14
結果………………………………………………………………………………………………………………………19
全基因表現數據分析嗎啡成癮影響的基因表現差異…………………………………………19
分析嗎啡成癮影響的信號路徑、基因表現與分子功能………………………………………20
嗎啡成癮促進PPAR signaling pathway、AMPK signaling pathway、cGMP-PKG signaling pathway相關基因大量表現…………………………………………………………………………………21
探討嗎啡成癮影響的機制造成PCG-1α表現下降………………………………………………..26
嗎啡成癮上調轉錄因子HNF4A，HNF4A調控下游Lipin1參與的脂肪酸代謝相關基因表現………………………………………………………………………………………………………………28
討論………………………………………………………………………………………………………………………31
附圖表……………………………………………………………………………………………………………………34
圖一、RNA-sequencing的前置RNA樣品配製…………………………………………………………34
圖二、全基因分析之Principal Component Analysis和Heatmap……………………………36
圖三、乳腺腫瘤中表現量高的基因聯集之KEGG pathway和GO-term enrichment analysis……………………………………………………………………………………………………………………39
圖五、表現增加的基因參與的生物功能與機制……………………………………………………44
圖六、分析嗎啡成癮造成PGC-1α表現減少的調控機制………………………………………46
圖七、嗎啡成癮降低下游LPIN1參與的脂肪酸代謝基因表現………………………………49
圖八、嗎啡成癮小鼠腫瘤之乳癌相關基因表現……………………………………………………50
圖九、公開數據庫中癌症與正常人類樣本的PGC-1α表現量差異………………………53
圖十、分析嗎啡成癮影響腫瘤微環境相關的基因………………………………………………54
圖十一、嗎啡成癮促進乳癌進程的示意圖……………………………………………………………55
參考資料………………………………………………………………………………………………………………56

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians 2018, 68(6):394-424.
2. Wild C, Weiderpass E, Stewart B: World cancer report: cancer research for cancer prevention. Lyon: International Agency for Research on Cancer 2020.
3. Lynch BM, Neilson HK, Friedenreich CM: Physical activity and breast cancer prevention. In: Physical activity and cancer. Springer; 2010: 13-42.
4. del Pilar Camacho-Leal M, Sciortino M, Cabodi S: ErbB2 receptor in breast cancer: Implications in cancer cell migration, invasion and resistance to targeted therapy. Breast Cancer Biol Med 2017.
5. Feng Y, Spezia M, Huang S, Yuan C, Zeng Z, Zhang L, Ji X, Liu W, Huang B, Luo W: Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes & diseases 2018, 5(2):77-106.
6. Al-thoubaity FK: Molecular classification of breast cancer: A retrospective cohort study. Annals of Medicine and Surgery 2020, 49:44-48.
7. Fragomeni SM, Sciallis A, Jeruss JS: Molecular subtypes and local-regional control of breast cancer. Surgical Oncology Clinics 2018, 27(1):95-120.
8. Koh J, Kim MJ: Introduction of a new staging system of breast cancer for radiologists: an emphasis on the prognostic stage. Korean journal of radiology 2019, 20(1):69-82.
9. MPH RLS, MPH KDM, Ahmedin Jemal DVM P: Cancer Statistics, 2020. CA: a cancer journal for clinicians 2020, 70(1):7-30.
10. Chiang AC, Massagué J: Molecular basis of metastasis. New England Journal of Medicine 2008, 359(26):2814-2823.
11. Jin X, Mu P: Targeting breast cancer metastasis. Breast cancer: basic and clinical research 2015, 9:BCBCR. S25460.
12. Gupta GP, Massagué J: Cancer metastasis: building a framework. Cell 2006, 127(4):679-695.
13. Kalluri R, Weinberg RA: The basics of epithelial-mesenchymal transition. The Journal of clinical investigation 2009, 119(6):1420-1428.
14. Yeung KT, Yang J: Epithelial–mesenchymal transition in tumor metastasis. Molecular oncology 2017, 11(1):28-39.
15. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. cell 2004, 117(7):927-939.
16. Pavlova NN, Thompson CB: The emerging hallmarks of cancer metabolism. Cell metabolism 2016, 23(1):27-47.
17. Warburg O, Wind F, Negelein E: The metabolism of tumors in the body. The Journal of general physiology 1927, 8(6):519.
18. Lucantoni F, Dussmann H, Prehn JH: Metabolic targeting of breast cancer cells with the 2-Deoxy-D-Glucose and the mitochondrial bioenergetics inhibitor MDIVI-1. Frontiers in Cell and Developmental Biology 2018, 6:113.
19. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM: A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998, 92(6):829-839.
20. Handschin C, Spiegelman BM: Peroxisome proliferator-activated receptor γ coactivator 1 coactivators, energy homeostasis, and metabolism. Endocrine reviews 2006, 27(7):728-735.
21. Bost F, Kaminski L: The metabolic modulator PGC-1α in cancer. American journal of cancer research 2019, 9(2):198.
22. Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP: Peroxisome proliferator–activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis. The Journal of clinical investigation 2000, 106(7):847-856.
23. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC: Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999, 98(1):115-124.
24. Kang I, Chu CT, Kaufman BA: The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms. FEBS letters 2018, 592(5):793-811.
25. Huss JM, Torra IP, Staels B, Giguere V, Kelly DP: Estrogen-related receptor α directs peroxisome proliferator-activated receptor α signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Molecular and cellular biology 2004, 24(20):9079-9091.
26. Vega RB, Huss JM, Kelly DP: The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor α in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Molecular and cellular biology 2000, 20(5):1868-1876.
27. Wende AR, Schaeffer PJ, Parker GJ, Zechner C, Han D-H, Chen MM, Hancock CR, Lehman JJ, Huss JM, McClain DA: A role for the transcriptional coactivator PGC-1α in muscle refueling. Journal of Biological Chemistry 2007, 282(50):36642-36651.
28. Wende AR, Huss JM, Schaeffer PJ, Giguere V, Kelly DP: PGC-1α coactivates PDK4 gene expression via the orphan nuclear receptor ERRα: a mechanism for transcriptional control of muscle glucose metabolism. Molecular and cellular biology 2005, 25(24):10684-10694.
29. Valle I, Álvarez-Barrientos A, Arza E, Lamas S, Monsalve M: PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovascular research 2005, 66(3):562-573.
30. Vazquez F, Lim J-H, Chim H, Bhalla K, Girnun G, Pierce K, Clish CB, Granter SR, Widlund HR, Spiegelman BM: PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer cell 2013, 23(3):287-301.
31. Luo C, Lim J-H, Lee Y, Granter SR, Thomas A, Vazquez F, Widlund HR, Puigserver P: A PGC1α-mediated transcriptional axis suppresses melanoma metastasis. Nature 2016, 537(7620):422-426.
32. Mullen AR, Wheaton WW, Jin ES, Chen P-H, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ: Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 2012, 481(7381):385-388.
33. McGuirk S, Gravel S-P, Deblois G, Papadopoli DJ, Faubert B, Wegner A, Hiller K, Avizonis D, Akavia UD, Jones RG: PGC-1α supports glutamine metabolism in breast cancer. Cancer & metabolism 2013, 1(1):1-11.
34. Klimcakova E, Chénard V, McGuirk S, Germain D, Avizonis D, Muller WJ, St-Pierre J: PGC-1α Promotes the Growth of ErbB2/Neu–Induced Mammary Tumors by Regulating Nutrient Supply. Cancer research 2012, 72(6):1538-1546.
35. LeBleu VS, O’Connell JT, Herrera KNG, Wikman H, Pantel K, Haigis MC, De Carvalho FM, Damascena A, Chinen LTD, Rocha RM: PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nature cell biology 2014, 16(10):992-1003.
36. Balkwill FR, Capasso M, Hagemann T: The tumor microenvironment at a glance. In.: The Company of Biologists Ltd; 2012.
37. Yu Y, Xiao C, Tan L, Wang Q, Li X, Feng Y: Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF-β signalling. British journal of cancer 2014, 110(3):724-732.
38. Zhao Y, Adjei AA: Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor. The oncologist 2015, 20(6):660.
39. Hicklin DJ, Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. Journal of clinical oncology 2005, 23(5):1011-1027.
40. Fang Y, Yan Y: Tumor Microenvironment-the Critical Element of Tumor Metastasis. Zhongguo Fei Ai Za Zhi 2015, 18(1).
41. Chen Q, Zhang XH-F, Massagué J: Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer cell 2011, 20(4):538-549.
42. Ribatti D, Crivellato E, Roccaro A, Ria R, Vacca A: Mast cell contribution to angiogenesis related to tumour progression. Clinical & Experimental Allergy 2004, 34(11):1660-1664.
43. Dushyanthen S, Beavis PA, Savas P, Teo ZL, Zhou C, Mansour M, Darcy PK, Loi S: Relevance of tumor-infiltrating lymphocytes in breast cancer. BMC medicine 2015, 13(1):202.
44. Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, Delgado A, Correa P, Brayer J, Sotomayor EM: Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer research 2004, 64(16):5839-5849.
45. Webster LR: The relationship between the mechanisms of action and safety profiles of intrathecal morphine and ziconotide: A review of the literature. Pain Medicine 2015, 16(7):1265-1277.
46. Pathan H, Williams J: Basic opioid pharmacology: an update. British journal of pain 2012, 6(1):11-16.
47. Waldhoer M, Bartlett SE, Whistler JL: Opioid receptors. Annual review of biochemistry 2004, 73(1):953-990.
48. Murphy PB BS, Barrett MJ.: Morphine. StatPearls [Internet] 2020.
49. Vahedi HSM, Hajebi H, Vahidi E, Nejati A, Saeedi M: Comparison between intravenous morphine versus fentanyl in acute pain relief in drug abusers with acute limb traumatic injury. World journal of emergency medicine 2019, 10(1):27.
50. Nersesyan H, Slavin KV: Current aproach to cancer pain management: Availability and implications of different treatment options. Therapeutics and clinical risk management 2007, 3(3):381.
51. Listos J, Łupina M, Talarek S, Mazur A, Orzelska-Górka J, Kotlińska J: The mechanisms involved in morphine addiction: an overview. International journal of molecular sciences 2019, 20(17):4302.
52. Cheng W-F, Chen L-K, Chen C-A, Chang M-C, Hsiao P-N, Su Y-N, Lee C-N, Jeng H-J, Hsieh C-Y, Sun W-Z: Chimeric DNA vaccine reverses morphine-induced immunosuppression and tumorigenesis. Molecular therapy 2006, 13(1):203-210.
53. Raghavendra V, Kulkarni SK: Reversal of morphine tolerance and dependence by melatonin: possible role of central and peripheral benzodiazepine receptors. Brain research 1999, 834(1-2):178-181.
54. Gupta K, Kshirsagar S, Chang L, Schwartz R, Law P-Y, Yee D, Hebbel RP: Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer research 2002, 62(15):4491-4498.
55. Franchi S, Panerai AE, Sacerdote P: Buprenorphine ameliorates the effect of surgery on hypothalamus–pituitary–adrenal axis, natural killer cell activity and metastatic colonization in rats in comparison with morphine or fentanyl treatment. Brain, behavior, and immunity 2007, 21(6):767-774.
56. Cheng S, Guo M, Liu Z, Fu Y, Wu H, Wang C, Cao M: Morphine promotes the angiogenesis of postoperative recurrent tumors and metastasis of dormant breast cancer cells. Pharmacology 2019, 104(5-6):276-286.
57. Pan W, Honglin Z, Fan R, Qingchun Z, Ruifeng S, Xingyu L, Jinghao L, Yongwen L, Ying L, Hongyu L: Research Progress of Epigenetics in Pathogenesis and Treatment of Malignant Tumors. Zhongguo Fei Ai Za Zhi 2020, 23(2).
58. Okano M, Bell DW, Haber DA, Li E: DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999, 99(3):247-257.
59. Peters S, Hlady R, Opavska J, Klinkebiel D, Pirruccello SJ, Talmon GA, Sharp JG, Wu L, Jaenisch R, Simpson M: Tumor suppressor functions of Dnmt3a and Dnmt3b in the prevention of malignant mouse lymphopoiesis. Leukemia 2014, 28(5):1138-1142.
60. Williams K, Christensen J, Helin K: DNA methylation: TET proteins—guardians of CpG islands? EMBO reports 2012, 13(1):28-35.
61. Vastenhouw NL, Schier AF: Bivalent histone modifications in early embryogenesis. Current opinion in cell biology 2012, 24(3):374-386.
62. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF: EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proceedings of the National Academy of Sciences 2003, 100(20):11606-11611.
63. Song JS, Kim YS, Kim DK, Park Si, Jang SJ: Global histone modification pattern associated with recurrence and disease‐free survival in non‐small cell lung cancer patients. Pathology international 2012, 62(3):182-190.
64. Liu H, Li Y, Li J, Liu Y, Cui B: H3K4me3 and Wdr82 are associated with tumor progression and a favorable prognosis in human colorectal cancer. Oncology letters 2018, 16(2):2125-2134.
65. Perez-Cadahia B, Drobic B, Khan P, Shivashankar CC, Davie JR: Current understanding and importance of histone phosphorylation in regulating chromatin biology. Current opinion in drug discovery & development 2010, 13(5):613.
66. Rui L, Emre NT, Kruhlak MJ, Chung H-J, Steidl C, Slack G, Wright GW, Lenz G, Ngo VN, Shaffer AL: Cooperative epigenetic modulation by cancer amplicon genes. Cancer cell 2010, 18(6):590-605.
67. Draker R, Sarcinella E, Cheung P: USP10 deubiquitylates the histone variant H2A. Z and both are required for androgen receptor-mediated gene activation. Nucleic acids research 2011, 39(9):3529-3542.
68. Humphries B, Wang Z, Yang C: MicroRNA regulation of epigenetic modifiers in breast Cancer. Cancers 2019, 11(7):897.
69. Pandey AK, Zhang Y, Zhang S, Li Y, Tucker-Kellogg G, Yang H, Jha S: TIP60-miR-22 axis as a prognostic marker of breast cancer progression. Oncotarget 2015, 6(38):41290.
70. Metsalu T, Vilo J: ClustVis: a web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap. Nucleic acids research 2015, 43(W1):W566-W570.
71. Park S-J, Yoon B-H, Kim S-K, Kim S-Y: GENT2: an updated gene expression database for normal and tumor tissues. BMC medical genomics 2019, 12(5):101.
72. Goldman M, Craft B, Brooks A, Zhu J, Haussler D: The UCSC Xena Platform for cancer genomics data visualization and interpretation. BioRxiv 2018:326470.
73. EWENS A, MIHICH E, EHRKE MJ: Distant metastasis from subcutaneously grown E0771 medullary breast adenocarcinoma. Anticancer research 2005, 25(6B):3905-3915.
74. Johnstone CN, Smith YE, Cao Y, Burrows AD, Cross RS, Ling X, Redvers RP, Doherty JP, Eckhardt BL, Natoli AL: Functional and molecular characterisation of EO771. LMB tumours, a new C57BL/6-mouse-derived model of spontaneously metastatic mammary cancer. Disease models & mechanisms 2015, 8(3):237-251.
75. Déliot N, Constantin B: Plasma membrane calcium channels in cancer: Alterations and consequences for cell proliferation and migration. Biochimica et Biophysica Acta (BBA)-Biomembranes 2015, 1848(10):2512-2522.
76. Prevarskaya N, Skryma R, Shuba Y: Calcium in tumour metastasis: new roles for known actors. Nature Reviews Cancer 2011, 11(8):609-618.
77. Lehners M, Dobrowinski H, Feil S, Feil R: cGMP signaling and vascular smooth muscle cell plasticity. Journal of cardiovascular development and disease 2018, 5(2):20.
78. Fallahian F, Karami‐Tehrani F, Salami S, Aghaei M: Cyclic GMP induced apoptosis via protein kinase G in oestrogen receptor‐positive and‐negative breast cancer cell lines. The FEBS journal 2011, 278(18):3360-3369.
79. Kahl CR, Means AR: Regulation of cell cycle progression by calcium/calmodulin-dependent pathways. Endocrine reviews 2003, 24(6):719-736.
80. Wang X, Prager BC, Wu Q, Kim LJ, Gimple RC, Shi Y, Yang K, Morton AR, Zhou W, Zhu Z: Reciprocal signaling between glioblastoma stem cells and differentiated tumor cells promotes malignant progression. Cell stem cell 2018, 22(4):514-528. e515.
81. Bach D-H, Park HJ, Lee SK: The dual role of bone morphogenetic proteins in cancer. Molecular Therapy-Oncolytics 2018, 8:1-13.
82. Tripolt S, Knab VM, Neubauer HA, Elmer DP, Aberger F, Moriggl R, Fux DA: Opioids trigger breast cancer metastasis through E-Cadherin downregulation and STAT3 activation promoting epithelial-mesenchymal transition. bioRxiv 2018:443663.
83. Wei YC, Zhang B, Li X, Liu XM, Zhang J, Lei B, Li B, Zhai R, Chen Q, Li Y: Upregulation and activation of δ‑opioid receptors promotes the progression of human breast cancer. Oncology reports 2016, 36(5):2579-2586.
84. Tang B, Li Y, Yuan S, Tomlinson S, He S: Upregulation of the δ opioid receptor in liver cancer promotes liver cancer progression both in vitro and in vivo. International journal of oncology 2013, 43(4):1281-1290.
85. Wang T, Qin Y, Lai H, Wei W, Li Z, Yang Y, Huang M, Chen J: The prognostic value of ADRA1 subfamily genes in gastric carcinoma. Oncology letters 2019, 18(3):3150-3158.
86. Harris AM, Warner BW, Wilson JM, Becker A, Rowland RG, Conner W, Lane M, Kimbler K, Durbin EB, Baron AT: Effect of α1-adrenoceptor antagonist exposure on prostate cancer incidence: an observational cohort study. The Journal of urology 2007, 178(5):2176-2180.
87. İşeri ÖD, Sahin FI, Terzi YK, Yurtcu E, Erdem SR, Sarialioglu F: beta-Adrenoreceptor antagonists reduce cancer cell proliferation, invasion, and migration. Pharmaceutical biology 2014, 52(11):1374-1381.
88. An R, Liu J, He J, Wang F, Zhang Q, Yu Q: PDE3A inhibitor anagrelide activates death signaling pathway genes and synergizes with cell death-inducing cytokines to selectively inhibit cancer cell growth. American journal of cancer research 2019, 9(9):1905.
89. Hao N, Shen W, Du R, Jiang S, Zhu J, Chen Y, Huang C, Shi Y, Xiang R, Luo Y: Phosphodiesterase 3A Represents a Therapeutic Target that Drives Stem Cell–like Property and Metastasis in Breast Cancer. Molecular Cancer Therapeutics 2020, 19(3):868-881.
90. Wang QM, Lv L, Tang Y, Zhang L, Wang LF: MMP‑1 is overexpressed in triple‑negative breast cancer tissues and the knockdown of MMP‑1 expression inhibits tumor cell malignant behaviors in vitro. Oncology letters 2019, 17(2):1732-1740.
91. Humphries JM, Penno MA, Weiland F, Klingler-Hoffmann M, Zuber A, Boussioutas A, Ernst M, Hoffmann P: Identification and validation of novel candidate protein biomarkers for the detection of human gastric cancer. Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics 2014, 1844(5):1051-1058.
92. Su F, Kozak KR, Imaizumi S, Gao F, Amneus MW, Grijalva V, Ng C, Wagner A, Hough G, Farias-Eisner G: Apolipoprotein AI (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer. Proceedings of the National Academy of Sciences 2010, 107(46):19997-20002.
93. Lin X, Hong S, Huang J, Chen Y, Chen Y, Wu Z: Plasma apolipoprotein A1 levels at diagnosis are independent prognostic factors in invasive ductal breast cancer. Discovery medicine 2017, 23(127):247-258.
94. Tougas C, Grindrod T, Cai L, Alkassis F, Kasahara H: Heterozygous Mylk3 knockout mice partially recapitulate human DCM with heterozygous MYLK3 mutations. Frontiers in physiology 2019, 10:696.
95. Phelps DL, Borley JV, Flower KJ, Dina R, Darb-Esfahani S, Braicu I, Sehouli J, Fotopoulou C, Wilhelm-Benartzi CS, Gabra H: Methylation of MYLK3 gene promoter region: a biomarker to stratify surgical care in ovarian cancer in a multicentre study. British journal of cancer 2017, 116(10):1287-1293.
96. Fan W, Evans R: PPARs and ERRs: molecular mediators of mitochondrial metabolism. Current opinion in cell biology 2015, 33:49-54.
97. Schlueter N, de Sterke A, Willmes DM, Spranger J, Jordan J, Birkenfeld AL: Metabolic actions of natriuretic peptides and therapeutic potential in the metabolic syndrome. Pharmacology & therapeutics 2014, 144(1):12-27.
98. Haas B, Mayer P, Jennissen K, Scholz D, Diaz MB, Bloch W, Herzig S, Fässler R, Pfeifer A: Protein kinase G controls brown fat cell differentiation and mitochondrial biogenesis. Science signaling 2009, 2(99):ra78-ra78.
99. Salem AF, Whitaker-Menezes D, Howell A, Sotgia F, Lisanti MP: Mitochondrial biogenesis in epithelial cancer cells promotes breast cancer tumor growth and confers autophagy resistance. Cell cycle 2012, 11(22):4174-4180.
100. Wang X, Moraes CT: Increases in mitochondrial biogenesis impair carcinogenesis at multiple levels. Molecular oncology 2011, 5(5):399-409.
101. Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S, Youle RJ, Mihara K: Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. Journal of Cell Biology 2010, 191(6):1141-1158.
102. Yu R, Liu T, Jin S-B, Ning C, Lendahl U, Nistér M, Zhao J: MIEF1/2 function as adaptors to recruit Drp1 to mitochondria and regulate the association of Drp1 with Mff. Scientific reports 2017, 7(1):1-16.
103. Scarpulla RC, Vega RB, Kelly DP: Transcriptional integration of mitochondrial biogenesis. Trends in Endocrinology & Metabolism 2012, 23(9):459-466.
104. Zhang Y, Zhang X, Wang J, Shen Y, Tang X, Yu F, Wang R: Expression and function of PPARs in cancer stem cells. Current stem cell research & therapy 2016, 11(3):226-234.
105. Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ, Zhang M, Fletcher C, Singer S, Spiegelman BM: Terminal differentiation of human breast cancer through PPARγ. Molecular cell 1998, 1(3):465-470.
106. Javelaud D, Alexaki VI, Dennler S, Mohammad KS, Guise TA, Mauviel A: TGF-β/SMAD/GLI2 signaling axis in cancer progression and metastasis. Cancer research 2011, 71(17):5606-5610.
107. Alexaki V-I, Javelaud D, Van Kempen LC, Mohammad KS, Dennler S, Luciani F, Hoek KS, Juàrez P, Goydos JS, Fournier PJ: GLI2-mediated melanoma invasion and metastasis. Journal of the National Cancer Institute 2010, 102(15):1148-1159.
108. Dennler S, André J, Alexaki I, Li A, Magnaldo T, Ten Dijke P, Wang X-J, Verrecchia F, Mauviel A: Induction of sonic hedgehog mediators by transforming growth factor-β: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer research 2007, 67(14):6981-6986.
109. Liu S, Dontu G, Mantle ID, Patel S, Ahn N-s, Jackson KW, Suri P, Wicha MS: Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer research 2006, 66(12):6063-6071.
110. Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, Van Belle PA, Xu X, Elder DE, Herlyn M: A tumorigenic subpopulation with stem cell properties in melanomas. Cancer research 2005, 65(20):9328-9337.
111. Fan L, Lei H, Lin Y, Zhou Z, Shu G, Yan Z, Yin G: CXCL13, FCRLA, PLA2G2D and MS4A1 Were Identified As Prognostic Biomarkers and Correlated with Immune Infiltration in Ovarian Cancer by Integrating TMB and Microenvironment Analysis. Available at SSRN 3514638 2020.
112. Ganesh K, Basnet H, Kaygusuz Y, Laughney AM, He L, Sharma R, O’Rourke KP, Reuter VP, Huang Y-H, Turkekul M: L1CAM defines the regenerative origin of metastasis-initiating cells in colorectal cancer. Nature Cancer 2020, 1(1):28-45.
113. Gavert N, Conacci-Sorrell M, Gast D, Schneider A, Altevogt P, Brabletz T, Ben-Ze'ev A: L1, a novel target of β-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers. The Journal of cell biology 2005, 168(4):633-642.
114. Bao S, Wu Q, Li Z, Sathornsumetee S, Wang H, McLendon RE, Hjelmeland AB, Rich JN: Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer research 2008, 68(15):6043-6048.
115. Jang BG, Kim HS, Chang WY, Bae JM, Kim WH, Kang GH: Expression profile of LGR5 and its prognostic significance in colorectal cancer progression. The American journal of pathology 2018, 188(10):2236-2250.
116. Cao H-Z, Liu X-F, Yang W-T, Chen Q, Zheng P-S: LGR5 promotes cancer stem cell traits and chemoresistance in cervical cancer. Cell death & disease 2017, 8(9):e3039-e3039.
117. Yang L, Tang H, Kong Y, Xie X, Chen J, Song C, Liu X, Ye F, Li N, Wang N: LGR5 Promotes Breast Cancer Progression and Maintains Stem‐Like Cells Through Activation of W nt/β‐Catenin Signaling. Stem cells 2015, 33(10):2913-2924.
118. Krämer AI, Handschin C: How Epigenetic Modifications Drive the Expression and Mediate the Action of PGC-1α in the Regulation of Metabolism. International journal of molecular sciences 2019, 20(21):5449.
119. Good CR, Panjarian S, Kelly AD, Madzo J, Patel B, Jelinek J, Issa J-PJ: TET1-mediated hypomethylation activates oncogenic signaling in triple-negative breast cancer. Cancer research 2018, 78(15):4126-4137.
120. Spangle JM, Dreijerink KM, Groner AC, Cheng H, Ohlson CE, Reyes J, Lin CY, Bradner J, Zhao JJ, Roberts TM: PI3K/AKT signaling regulates H3K4 methylation in breast cancer. Cell reports 2016, 15(12):2692-2704.
121. Li S, Shen L, Chen KN: Association between H3K4 methylation and cancer prognosis: A meta‐analysis. Thoracic Cancer 2018, 9(7):794-799.
122. Wang H, Peiris TH, Mowery A, Le Lay J, Gao Y, Greenbaum LE: CCAAT/enhancer binding protein-β is a transcriptional regulator of peroxisome-proliferator-activated receptor-γ coactivator-1α in the regenerating liver. Molecular endocrinology 2008, 22(7):1596-1605.
123. Du Q, Tan Z, Shi F, Tang M, Xie L, Zhao L, Li Y, Hu J, Zhou M, Bode A: PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation. Cancer science 2019, 110(6):2050.
124. Irrcher I, Ljubicic V, Kirwan AF, Hood DA: AMP-activated protein kinase-regulated activation of the PGC-1α promoter in skeletal muscle cells. PloS one 2008, 3(10):e3614.
125. Irrcher I, Ljubicic V, Hood DA: Interactions between ROS and AMP kinase activity in the regulation of PGC-1α transcription in skeletal muscle cells. American Journal of Physiology-Cell Physiology 2009, 296(1):C116-C123.
126. Yoboue ED, Devin A: Reactive oxygen species-mediated control of mitochondrial biogenesis. International journal of cell biology 2012, 2012.
127. Valcarcel-Jimenez L, Macchia A, Crosas-Molist E, Schaub-Clerigué A, Camacho L, Martín-Martín N, Cicogna P, Viera-Bardón C, Fernández-Ruiz S, Rodriguez-Hernandez I: PGC1α suppresses prostate cancer cell invasion through ERRα transcriptional control. Cancer Research 2019, 79(24):6153-6165.
128. LaGory EL, Wu C, Taniguchi CM, Ding C-KC, Chi J-T, von Eyben R, Scott DA, Richardson AD, Giaccia AJ: Suppression of PGC-1a Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma. Cell Reports 2015, 12(4):717.
129. Jiang WG, Douglas‐Jones A, Mansel RE: Expression of peroxisome‐proliferator activated receptor‐gamma (PPARγ) and the PPARγ co‐activator, PGC‐1, in human breast cancer correlates with clinical outcomes. International journal of cancer 2003, 106(5):752-757.
130. Chiang JY: Hepatocyte nuclear factor 4α regulation of bile acid and drug metabolism. Expert opinion on drug metabolism & toxicology 2009, 5(2):137-147.
131. Chen Z, Gropler MC, Mitra MS, Finck BN: Complex interplay between the lipin 1 and the hepatocyte nuclear factor 4 α (HNF4α) pathways to regulate liver lipid metabolism. PloS one 2012, 7(12):e51320.
132. Rhee J, Ge H, Yang W, Fan M, Handschin C, Cooper M, Lin J, Li C, Spiegelman BM: Partnership of PGC-1α and HNF4α in the regulation of lipoprotein metabolism. Journal of Biological Chemistry 2006, 281(21):14683-14690.
133. Brohée L, Demine S, Willems J, Arnould T, Colige AC, Deroanne CF: Lipin-1 regulates cancer cell phenotype and is a potential target to potentiate rapamycin treatment. Oncotarget 2015, 6(13):11264.
134. Kok B, Brindley D: The Role of Phosphatidate Phosphatase in Glycerolipid Biosynthesis. Regulation of Lipins and Their Role in Lipid Metabolism”; AOCS Lipid Library: Urbana, IL, USA 2010.
135. Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence Jr JC, Kelly DP: Lipin 1 is an inducible amplifier of the hepatic PGC-1α/PPARα regulatory pathway. Cell metabolism 2006, 4(3):199-210.
136. Alluri P, Newman LA: Basal-like and triple-negative breast cancers: searching for positives among many negatives. Surgical Oncology Clinics 2014, 23(3):567-577.
137. Prat A, Adamo B, Cheang MC, Anders CK, Carey LA, Perou CM: Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. The oncologist 2013, 18(2):123.
138. Nguyen J, Luk K, Vang D, Soto W, Vincent L, Robiner S, Saavedra R, Li Y, Gupta P, Gupta K: Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer. British journal of anaesthesia 2014, 113(suppl_1):i4-i13.
139. Po A, Silvano M, Miele E, Capalbo C, Eramo A, Salvati V, Todaro M, Besharat Z, Catanzaro G, Cucchi D: Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma. Oncogene 2017, 36(32):4641-4652.
140. Thomas Z, Gibson W, Sexton J, Aird K, Ingram S, Aldrich A, Lyerly H, Devi G, Williams K: Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration. British journal of cancer 2011, 104(10):1575-1586.
141. Sablé-Amplis R, Agid R, Abadie D: Some effects of morphine on lipid metabolism in normal, tolerant and abstinent rats. Life Sciences 1975, 16(9):1477-1482.
142. Balaban S, Lee LS, Schreuder M, Hoy AJ: Obesity and cancer progression: is there a role of fatty acid metabolism? BioMed research international 2015, 2015.
143. Samovski D, Sun J, Pietka T, Gross RW, Eckel RH, Su X, Stahl PD, Abumrad NA: Regulation of AMPK activation by CD36 links fatty acid uptake to β-oxidation. Diabetes 2015, 64(2):353-359.
144. Uray IP, Liang Y, Hyder SM: Estradiol down-regulates CD36 expression in human breast cancer cells. Cancer letters 2004, 207(1):101-107.
145. Farooqui M, Poonawala T, Griffin RW, Nguyen J, Hebbel RP, Gupta K: Mu opioid receptor stimulates a growth promoting and pro-angiogenic tumor microenvironment. In.: AACR; 2005.
146. Tajbakhsh A, Mokhtari‐Zaer A, Rezaee M, Afzaljavan F, Rivandi M, Hassanian SM, Ferns GA, Pasdar A, Avan A: Therapeutic potentials of BDNF/TrkB in breast cancer; current status and perspectives. Journal of cellular biochemistry 2017, 118(9):2502-2515.
147. Cheng Z, Zhang D, Gong B, Wang P, Liu F: CD163 as a novel target gene of STAT3 is a potential therapeutic target for gastric cancer. Oncotarget 2017, 8(50):87244.
148. Morandi F, Horenstein AL, Costa F, Giuliani N, Pistoia V, Malavasi F: CD38: a target for immunotherapeutic approaches in multiple myeloma. Frontiers in immunology 2018, 9:2722.
149. Gilkes DM, Semenza GL: Role of hypoxia-inducible factors in breast cancer metastasis. Future oncology 2013, 9(11):1623-1636.
150. Calzada M, Del Peso L: Hypoxia-inducible factors and cancer. Clinical and Translational Oncology 2007, 9(5):278-289.
151. Zaynagetdinov R, Sherrill TP, Gleaves LA, McLoed AG, Saxon JA, Habermann AC, Connelly L, Dulek D, Peebles RS, Fingleton B: Interleukin-5 facilitates lung metastasis by modulating the immune microenvironment. Cancer research 2015, 75(8):1624-1634.
152. Behzadian MA, Windsor LJ, Ghaly N, Liou G, Tsai NT, Caldwell RB: VEGF‐induced paracellular permeability in cultured endothelial cells involves urokinase and its receptor. The FASEB Journal 2003, 17(6):752-754.
153. Zhang Q, Lu S, Li T, Yu L, Zhang Y, Zeng H, Qian X, Bi J, Lin Y: ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. Journal of Experimental & Clinical Cancer Research 2019, 38(1):1-12.
154. Wang J, Li D, Cang H, Guo B: Crosstalk between cancer and immune cells: Role of tumor‐associated macrophages in the tumor microenvironment. Cancer medicine 2019, 8(10):4709-4721.
155. Di Carlo E, Forni G, Lollini P, Colombo MP, Modesti A, Musiani P: The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood, The Journal of the American Society of Hematology 2001, 97(2):339-345.