MicroRNA-96: A therapeutic and diagnostic tumor marker

Document Type : Review Article

Authors

Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Cancer has been always considered as one of the main human health challenges worldwide. One of the main causes of cancer-related mortality is late diagnosis in the advanced stages of the disease, which reduces the therapeutic efficiency. Therefore, novel non-invasive diagnostic methods are required for the early detection of tumors and improving the quality of life and survival in cancer patients. MicroRNAs (miRNAs) have pivotal roles in various cellular processes such as cell proliferation, motility, and neoplastic transformation. Since circulating miRNAs have high stability in body fluids, they can be suggested as efficient noninvasive tumor markers. MiR-96 belongs to the miR-183-96-182 cluster that regulates cell migration and tumor progression as an oncogene or tumor suppressor by targeting various genes in solid tumors. In the present review, we have summarized all of the studies that assessed the role of miR-96 during tumor progression. This review clarifies the molecular mechanisms and target genes recruited by miR-96 to regulate tumor progression and metastasis. It was observed that miR-96 mainly affects tumorigenesis by targeting the structural proteins and FOXO transcription factors.

Keywords


1. Chen J, Zhang K, Xu Y, Gao Y, Li C, Wang R, et al. The role of microRNA-26a in human cancer progression and clinical application. Tumour Biol 2016; 37:7095-7108.
2. Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 2009; 10:704-714.
3. Cheng G. Circulating miRNAs: Roles in cancer diagnosis, prognosis and therapy. Adv Drug Deliv Rev 2015; 81:75-93.
4. Berindan-Neagoe I, Monroig Pdel C, Pasculli B, Calin GA. MicroRNAome genome: A treasure for cancer diagnosis and therapy. CA Cancer J Clin 2014; 64:311-336.
5. Cuk K, Zucknick M, Heil J, Madhavan D, Schott S, Turchinovich A, et al. Circulating microRNAs in plasma as early detection markers for breast cancer. Int J Cancer 2013; 132:1602-1612.
6. Gorur A, Balci Fidanci S, Dogruer Unal N, Ayaz L, Akbayir S, Yildirim Yaroglu H, et al. Determination of plasma microRNA for early detection of gastric cancer. Mol Biol Rep 2013; 40:2091-2096.
7. Guo Y, Liu H, Zhang H, Shang C, Song Y. miR-96 regulates FOXO1-mediated cell apoptosis in bladder cancer. Oncol Lett 2012; 4:561-565.
8. Li Z, Wang Y. miR-96 targets SOX6 and promotes proliferation, migration, and invasion of hepatocellular carcinoma. Biochem Cell Biol 2018; 96:365-371.
9. Li XL, Hara T, Choi Y, Subramanian M, Francis P, Bilke S, et al. A p21-ZEB1 complex inhibits epithelial-mesenchymal transition through the microRNA 183-96-182 cluster. Mol Cell Biol 2014; 34:533-550.
10. Tang X, Zheng D, Hu P, Zeng Z, Li M, Tucker L, et al. Glycogen synthase kinase 3 beta inhibits microRNA-183-96-182 cluster via the beta-Catenin/TCF/LEF-1 pathway in gastric cancer cells. Nucleic Acids Res 2014; 42:2988-2998.
11. Tsai YC, Chen WY, Siu MK, Tsai HY, Yin JJ, Huang J, et al. Epidermal growth factor receptor signaling promotes metastatic prostate cancer through microRNA-96-mediated downregulation of the tumor suppressor ETV6. Cancer Lett 2017; 384:1-8.
12. Hunter KW. Ezrin, a key component in tumor metastasis. Trends Mol Med 2004; 10:201-204.
13. Yao Q, Pei Y, Zhang X, Xie B. microRNA-96 acts as a tumor suppressor gene in human osteosarcoma via target regulation of EZRIN. Life Sci 2018; 203:1-11.
14. Yu N, Fu S, Liu Y, Xu Z, Liu Y, Hao J, et al. miR-96 suppresses renal cell carcinoma invasion via downregulation of Ezrin expression. J Exp Clin Cancer Res 2015; 34:107.
15. Tanaka-Okamoto M, Hori K, Ishizaki H, Hosoi A, Itoh Y, Wei M, et al. Increased susceptibility to spontaneous lung cancer in mice lacking LIM-domain only 7. Cancer Sci 2009; 100:608-616.
16. Kang S, Xu H, Duan X, Liu JJ, He Z, Yu F, et al. PCD1, a novel gene containing PDZ and LIM domains, is overexpressed in several human cancers. Cancer Res 2000; 60:5296-5302.
17. Wu H, Zhou J, Mei S, Wu D, Mu Z, Chen B, et al. Circulating exosomal microRNA-96 promotes cell proliferation, migration and drug resistance by targeting LMO7. J Cell Mol Med 2017; 21:1228-1236.
18. Gao XH, Zhang YL, Zhang ZY, Guo SS, Chen XB, Guo YZ. MicroRNA-96-5p represses breast cancer proliferation and invasion through Wnt/beta-catenin signaling via targeting CTNND1. Sci Rep 2020; 10:44.
19. Xie F, Ye L, Ta M, Zhang L, Jiang WG. MTSS1: a multifunctional protein and its role in cancer invasion and metastasis. Front Biosci (Schol Ed) 2011; 3:621-631.
20. Huang XY, Huang ZL, Xu B, Chen Z, Re TJ, Zheng Q, et al. Elevated MTSS1 expression associated with metastasis and poor prognosis of residual hepatitis B-related hepatocellular carcinoma. J Exp Clin Cancer Res 2016; 35:85.
21. Li XD, Zhang JX, Jiang LJ, Wang FW, Liu LL, Liao YJ, et al. Overexpression of maelstrom promotes bladder urothelial carcinoma cell aggressiveness by epigenetically downregulating MTSS1 through DNMT3B. Oncogene 2016; 35:6281-6292.
22. Yin X, Chai Z, Sun X, Chen J, Wu X, Yang L, et al. Overexpression of microRNA-96 is associated with poor prognosis and promotes proliferation, migration and invasion in cholangiocarcinoma cells via MTSS1. Exp Ther Med 2020; 19:2757-2765.
23. Xie W, Sun F, Chen L, Cao X. miR-96 promotes breast cancer metastasis by suppressing MTSS1. Oncol Lett 2018; 15:3464-3471.
24. Xu L, Zhong J, Guo B, Zhu Q, Liang H, Wen N, et al. miR-96 promotes the growth of prostate carcinoma cells by suppressing MTSS1. Tumour Biol 2016; 37:12023-12032.
25. Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet 2014; 15:7-21.
26. Gordon FE, Nutt CL, Cheunsuchon P, Nakayama Y, Provencher KA, Rice KA, et al. Increased expression of angiogenic genes in the brains of mouse meg3-null embryos. Endocrinology 2010; 151:2443-2452.
27. Kruer TL, Dougherty SM, Reynolds L, Long E, de Silva T, Lockwood WW, et al. Expression of the lncRNA maternally expressed gene 3 (MEG3) contributes to the control of lung cancer cell proliferation by the Rb pathway. PLoS One 2016; 11:e0166363.
28. Zhang S, Guo W. Long noncoding RNA MEG3 suppresses the growth of glioma cells by regulating the miR965p/MTSS1 signaling pathway. Mol Med Rep 2019; 20:4215-4225.
29. Lu KH, Li W, Liu XH, Sun M, Zhang ML, Wu WQ, et al. Long non-coding RNA MEG3 inhibits NSCLC cells proliferation and induces apoptosis by affecting p53 expression. BMC Cancer 2013; 13:461.
30. Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R, et al. Activation of p53 by MEG3 non-coding RNA. J Biol Chem 2007; 282:24731-24742.
31. Qi L, Bart J, Tan LP, Platteel I, Sluis T, Huitema S, et al. Expression of miR-21 and its targets (PTEN, PDCD4, TM1) in flat epithelial atypia of the breast in relation to ductal carcinoma in situ and invasive carcinoma. BMC Cancer 2009; 9:163.
32. Nijak A, Alaerts M, Kuiperi C, Corveleyn A, Suys B, Paelinck B, et al. Left ventricular non-compaction with Ebstein anomaly attributed to a TPM1 mutation. Eur J Med Genet 2018; 61:8-10.
33. Liu G, Zhao X, Zhou J, Cheng X, Ye Z, Ji Z. Long non-coding RNA MEG3 suppresses the development of bladder urothelial carcinoma by regulating miR-96 and TPM1. Cancer Biol Ther 2018; 19:1039-1056.
34. Ge T, Xiang P, Mao H, Tang S, Zhou J, Zhang Y. Inhibition of miR-96 enhances the sensitivity of colorectal cancer cells to oxaliplatin by targeting TPM1. Exp Ther Med 2020; 20:2134-2140.
35. Wang S, Qiu Y, Bai B. The expression, regulation, and biomarker potential of glypican-1 in cancer. Front Oncol 2019; 9:614.
36. Li C, Du X, Tai S, Zhong X, Wang Z, Hu Z, et al. GPC1 regulated by miR-96-5p, rather than miR-182-5p, in inhibition of pancreatic carcinoma cell proliferation. Int J Mol Sci 2014; 15:6314-6327.
37. Bernfield M, Gotte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, et al. Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 1999; 68:729-777.
38. Cai Z, Grobe K, Zhang X. Role of heparan sulfate proteoglycans in optic disc and stalk morphogenesis. Dev Dyn 2014; 243:1310-1316.
39. Fei X, Zhang J, Zhao Y, Sun M, Zhao H, Li S. miR-96 promotes invasion and metastasis by targeting GPC3 in non-small cell lung cancer cells. Oncol Lett 2018; 15:9081-9086.
40. Chidlow JH, Jr., Sessa WC. Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation. Cardiovasc Res 2010; 86:219-225.
41. Cohen AW, Hnasko R, Schubert W, Lisanti MP. Role of caveolae and caveolins in health and disease. Physiol Rev 2004; 84:1341-1379.
42. Ayala G, Morello M, Frolov A, You S, Li R, Rosati F, et al. Loss of caveolin-1 in prostate cancer stroma correlates with reduced relapse-free survival and is functionally relevant to tumour progression. J Pathol 2013; 231:77-87.
43. Kannan A, Krishnan A, Ali M, Subramaniam S, Halagowder D, Sivasithamparam ND. Caveolin-1 promotes gastric cancer progression by up-regulating epithelial to mesenchymal transition by crosstalk of signalling mechanisms under hypoxic condition. Eur J Cancer 2014; 50:204-215.
44. Liu B, Zhang J, Yang D. miR-96-5p promotes the proliferation and migration of ovarian cancer cells by suppressing Caveolae1. J Ovarian Res 2019; 12:57.
45. Fraser SP, Diss JK, Chioni AM, Mycielska ME, Pan H, Yamaci RF, et al. Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Clin Cancer Res 2005; 11:5381-5389.
46. Kunzelmann K. Ion channels and cancer. J Membr Biol 2005; 205:159-173.
47. Afrasiabi E, Hietamaki M, Viitanen T, Sukumaran P, Bergelin N, Tornquist K. Expression and significance of HERG (KCNH2) potassium channels in the regulation of MDA-MB-435S melanoma cell proliferation and migration. Cell Signal 2010; 22:57-64.
48. Shao XD, Wu KC, Guo XZ, Xie MJ, Zhang J, Fan DM. Expression and significance of HERG protein in gastric cancer. Cancer Biol Ther 2008; 7:45-50.
49. Lastraioli E, Guasti L, Crociani O, Polvani S, Hofmann G, Witchel H, et al. herg1 gene and HERG1 protein are overexpressed in colorectal cancers and regulate cell invasion of tumor cells. Cancer Res 2004; 64:606-611.
50. Pillozzi S, Brizzi MF, Bernabei PA, Bartolozzi B, Caporale R, Basile V, et al. VEGFR-1 (FLT-1), beta1 integrin, and hERG K+ channel for a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome. Blood 2007; 110:1238-1250.
51. Feng J, Yu J, Pan X, Li Z, Chen Z, Zhang W, et al. HERG1 functions as an oncogene in pancreatic cancer and is downregulated by miR-96. Oncotarget 2014; 5:5832-5844.
52. Kikkert M, Doolman R, Dai M, Avner R, Hassink G, van Voorden S, et al. Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum. J Biol Chem 2004; 279:3525-3534.
53. Gao Z, Wang H, Li H, Li M, Wang J, Zhang W, et al. Long non-coding RNA CASC2 inhibits breast cancer cell growth and metastasis through the regulation of the miR-96-5p/SYVN1 pathway. Int J Oncol 2018; 53:2081-2090.
54. Gao J, Huo L, Sun X, Liu M, Li D, Dong JT, et al. The tumor suppressor CYLD regulates microtubule dynamics and plays a role in cell migration. J Biol Chem 2008; 283:8802-8809.
55. Gao J, Sun L, Huo L, Liu M, Li D, Zhou J. CYLD regulates angiogenesis by mediating vascular endothelial cell migration. Blood 2010; 115:4130-4137.
56. Wickstrom SA, Masoumi KC, Khochbin S, Fassler R, Massoumi R. CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin. EMBO J 2010; 29:131-144.
57. Zhao M, Xin XF, Zhang JY, Dai W, Lv TF, Song Y. LncRNA GMDS-AS1 inhibits lung adenocarcinoma development by regulating miR-96-5p/CYLD signaling. Cancer Med 2020; 9:1196-1208.
58. Wei S, Zheng Y, Jiang Y, Li X, Geng J, Shen Y, et al. The circRNA circPTPRA suppresses epithelial-mesenchymal transitioning and metastasis of NSCLC cells by sponging miR-96-5p. EBioMedicine 2019; 44:182-193.
59. Liu ZM, Wu ZY, Li WH, Wang LQ, Wan JN, Zhong Y. MiR-96-5p promotes the proliferation, invasion and metastasis of papillary thyroid carcinoma through down-regulating CCDC67. Eur Rev Med Pharmacol Sci 2019; 23:3421-3430.
60. Kaufmann E, Knochel W. Five years on the wings of fork head. Mech Dev 1996; 57:3-20.
61. Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer 2007; 7:847-859.
62. Kousteni S. FoxO1: a molecule for all seasons. J Bone Miner Res 2011; 26:912-917.
63. Kops GJ, Medema RH, Glassford J, Essers MA, Dijkers PF, Coffer PJ, et al. Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Mol Cell Biol 2002; 22:2025-2036.
64. Schmidt M, Fernandez de Mattos S, van der Horst A, Klompmaker R, Kops GJ, Lam EW, et al. Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol 2002; 22:7842-7852.
65. Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 2000; 10:1201-1204.
66. Modur V, Nagarajan R, Evers BM, Milbrandt J. FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J Biol Chem 2002; 277:47928-47937.
67. Brunet A, Kanai F, Stehn J, Xu J, Sarbassova D, Frangioni JV, et al. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J Cell Biol 2002; 156:817-828.
68. Kim SJ, Winter K, Nian C, Tsuneoka M, Koda Y, McIntosh CH. Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression. J Biol Chem 2005; 280:22297-22307.
69. Machida S, Spangenburg EE, Booth FW. Forkhead transcription factor FoxO1 transduces insulin-like growth factor’s signal to p27Kip1 in primary skeletal muscle satellite cells. J Cell Physiol 2003; 196:523-531.
70. Hou T, Ou J, Zhao X, Huang X, Huang Y, Zhang Y. MicroRNA-196a promotes cervical cancer proliferation through the regulation of FOXO1 and p27Kip1. Br J Cancer 2014; 110:1260-1268.
71. Zaballos MA, Santisteban P. FOXO1 controls thyroid cell proliferation in response to TSH and IGF-I and is involved in thyroid tumorigenesis. Mol Endocrinol 2013; 27:50-62.
72. Song HM, Luo Y, Li DF, Wei CK, Hua KY, Song JL, et al. MicroRNA-96 plays an oncogenic role by targeting FOXO1 and regulating AKT/FOXO1/Bim pathway in papillary thyroid carcinoma cells. Int J Clin Exp Pathol 2015; 8:9889-9900.
73. Yang N, Zhou J, Li Q, Han F, Yu Z. miR-96 exerts carcinogenic effect by activating AKT/GSK-3beta/beta-catenin signaling pathway through targeting inhibition of FOXO1 in hepatocellular carcinoma. Cancer Cell Int 2019; 19:38.
74. Fendler A, Jung M, Stephan C, Erbersdobler A, Jung K, Yousef GM. The antiapoptotic function of miR-96 in prostate cancer by inhibition of FOXO1. PLoS One 2013; 8:e80807.
75. Yang L, Liu L, Zhang X, Zhu Y, Li L, Wang B, et al. miR-96 enhances the proliferation of cervical cancer cells by targeting FOXO1. Pathol Res Pract 2020; 216:152854.
76. Lang C, Xu M, Zhao Z, Chen J, Zhang L. MicroRNA-96 expression induced by low-dose cisplatin or doxorubicin regulates chemosensitivity, cell death and proliferation in gastric cancer SGC7901 cells by targeting FOXO1. Oncol Lett 2018; 16:4020-4026.
77. Yu JJ, Wu YX, Zhao FJ, Xia SJ. miR-96 promotes cell proliferation and clonogenicity by down-regulating of FOXO1 in prostate cancer cells. Med Oncol 2014; 31:910.
78. Huang H, Tindall DJ. Dynamic FoxO transcription factors. J Cell Sci 2007; 120:2479-2487.
79. Lin H, Dai T, Xiong H, Zhao X, Chen X, Yu C, et al. Unregulated miR-96 induces cell proliferation in human breast cancer by downregulating transcriptional factor FOXO3a. PLoS One 2010; 5:e15797.
80. Zhou Y, Chen Y, Ding W, Hua Z, Wang L, Zhu Y, et al. LncRNA UCA1 impacts cell proliferation, invasion, and migration of pancreatic cancer through regulating miR-96/FOXO3. IUBMB Life 2018; 70:276-290.
81. Li J, Li P, Chen T, Gao G, Chen X, Du Y, et al. Expression of microRNA-96 and its potential functions by targeting FOXO3 in non-small cell lung cancer. Tumour Biol 2015; 36:685-692.
82. Yin Z, Wang W, Qu G, Wang L, Wang X, Pan Q. MiRNA-96-5p impacts the progression of breast cancer through targeting FOXO3. Thorac Cancer 2020; 11:956-963.
83. Gao F, Wang W. MicroRNA-96 promotes the proliferation of colorectal cancer cells and targets tumor protein p53 inducible nuclear protein 1, forkhead box protein O1 (FOXO1) and FOXO3a. Mol Med Rep 2015; 11:1200-1206.
84. Cai J, Tian AX, Wang QS, Kong PZ, Du X, Li XQ, et al. FOXF2 suppresses the FOXC2-mediated epithelial-mesenchymal transition and multidrug resistance of basal-like breast cancer. Cancer Lett 2015; 367:129-137.
85. Higashimori A, Dong Y, Zhang Y, Kang W, Nakatsu G, Ng SSM, et al. Forkhead box F2 suppresses gastric cancer through a novel FOXF2-IRF2BPL-beta-catenin signaling axis. Cancer Res 2018; 78:1643-1656.
86. Zhang Y, Wang X, Wang Z, Tang H, Fan H, Guo Q. miR-182 promotes cell growth and invasion by targeting forkhead box F2 transcription factor in colorectal cancer. Oncol Rep 2015; 33:2592-2598.
87. Simpson-Haidaris PJ, Rybarczyk B. Tumors and fibrinogen. The role of fibrinogen as an extracellular matrix protein. Ann N Y Acad Sci 2001; 936:406-425.
88. Vihinen P, Kahari VM. Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int J Cancer 2002; 99:157-166.
89. Wang H, Ma N, Li W, Wang Z. MicroRNA-96-5p promotes proliferation, invasion and EMT of oral carcinoma cells by directly targeting FOXF2. Biol Open 2020; 9.
90. Wei WR, Zeng GJ, Liu C, Zou BW, Li L. Overexpression of miR-96 promotes cell proliferation by targeting FOXF2 in prostate cancer. Int J Clin Exp Pathol 2017; 10:7596-7602.
91. Abbaszadegan MR, Riahi A, Forghanifard MM, Moghbeli M. WNT and NOTCH signaling pathways as activators for epidermal growth factor receptor in esophageal squamous cell carcinoma. Cell Mol Biol Lett 2018; 23:42.
92. Moghbeli M, Abbaszadegan MR, Golmakani E, Forghanifard MM. Correlation of Wnt and NOTCH pathways in esophageal squamous cell carcinoma. J Cell Commun Signal 2016; 10:129-135.
93. Yan Z, Wang J, Wang C, Jiao Y, Qi W, Che S. miR-96/HBP1/Wnt/beta-catenin regulatory circuitry promotes glioma growth. FEBS Lett 2014; 588:3038-3046.
94. Bafico A, Gazit A, Pramila T, Finch PW, Yaniv A, Aaronson SA. Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling. J Biol Chem 1999; 274:16180-16187.
95. Zhang H, Chen R, Shao J. MicroRNA-96-5p facilitates the viability, migration, and invasion and suppresses the apoptosis of cervical cancer cells bynegatively modulating SFRP4. Technol Cancer Res Treat 2020; 19:1533033820934132.
96. Moghbeli M, Rad A, Farshchian M, Taghehchian N, Gholamin M, Abbaszadegan MR. Correlation between meis1 and msi1 in esophageal squamous cell carcinoma. J Gastrointest Cancer 2016; 47:273-277.
97. Moghbeli M, Sadrizadeh A, Forghanifard MM, Mozaffari HM, Golmakani E, Abbaszadegan MR. Role of Msi1 and PYGO2 in esophageal squamous cell carcinoma depth of invasion. J Cell Commun Signal 2016; 10:49-53.
98. Rankin EB, Giaccia AJ. Hypoxic control of metastasis. Science 2016; 352:175-180.
99. Lu X, Kang Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res 2010; 16:5928-5935.
100. Shih JW, Chiang WF, Wu ATH, Wu MH, Wang LY, Yu YL, et al. Long noncoding RNA LncHIFCAR/MIR31HG is a HIF-1alpha co-activator driving oral cancer progression. Nat Commun 2017; 8:15874.
101. Guo Z, Wang X, Yang Y, Chen W, Zhang K, Teng B, et al. Hypoxic tumor-derived exosomal long noncoding RNA UCA1 promotes angiogenesis via miR-96-5p/AMOTL2 in pancreatic cancer. Mol Ther Nucleic Acids 2020; 22:179-195.
102. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2:442-454.
103. Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004; 431:707-712.
104. Shin SY, Rath O, Zebisch A, Choo SM, Kolch W, Cho KH. Functional roles of multiple feedback loops in extracellular signal-regulated kinase and Wnt signaling pathways that regulate epithelial-mesenchymal transition. Cancer Res 2010; 70:6715-6724.
105. Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A. TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell 2005; 16:1987-2002.
106. Yoo BK, Chen D, Su ZZ, Gredler R, Yoo J, Shah K, et al. Molecular mechanism of chemoresistance by astrocyte elevated gene-1. Cancer Res 2010; 70:3249-3258.
107. Robertson CL, Srivastava J, Rajasekaran D, Gredler R, Akiel MA, Jariwala N, et al. The role of AEG-1 in the development of liver cancer. Hepat Oncol 2015; 2:303-312.
108. Feng S, Yao J, Zhang Z, Zhang Y, Zhang Z, Liu J, et al. miR96 inhibits EMT by targeting AEG1 in glioblastoma cancer cells. Mol Med Rep 2018; 17:2964-2972.
109. Chang S, Bok P, Tsai CY, Sun CP, Liu H, Deussing JM, et al. NPTX2 is a key component in the regulation of anxiety. Neuropsychopharmacology 2018; 43:1943-1953.
110. Xu C, Tian G, Jiang C, Xue H, Kuerbanjiang M, Sun L, et al. NPTX2 promotes colorectal cancer growth and liver metastasis by the activation of the canonical Wnt/beta-catenin pathway via FZD6. Cell Death Dis 2019; 10:217.
111. Xiang W, Han L, Mo G, Lin L, Yu X, Chen S, et al. MicroRNA-96 is a potential tumor repressor by inhibiting NPTX2 in renal cell carcinoma. J Cell Biochem 2020; 121:1504-1513.
112. Shao S, Wang C, Wang S, Zhang H, Zhang Y. LncRNA STXBP5-AS1 suppressed cervical cancer progression via targeting miR-96-5p/PTEN axis. Biomed Pharmacother 2019; 117:109082.
113. Vahabi M, Pulito C, Sacconi A, Donzelli S, D’Andrea M, Manciocco V, et al. miR-96-5p targets PTEN expression affecting radio-chemosensitivity of HNSCC cells. J Exp Clin Cancer Res 2019; 38:141.
114. Iwashita H, Okudela K, Matsumura M, Yamanaka S, Sawazumi T, Enaka M, et al. Succinate dehydrogenase B-deficient renal cell carcinoma: A case report with novel germline mutation. Pathol Int 2017; 67:585-589.
115. Miettinen M, Lasota J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. Int J Biochem Cell Biol 2014; 53:514-519.
116. Fuhrmann DC, Wittig I, Brune B. TMEM126B deficiency reduces mitochondrial SDH oxidation by LPS, attenuating HIF-1alpha stabilization and IL-1beta expression. Redox Biol 2019; 20:204-216.
117. Loriot C, Domingues M, Berger A, Menara M, Ruel M, Morin A, et al. Deciphering the molecular basis of invasiveness in Sdhb-deficient cells. Oncotarget 2015; 6:32955-32965.
118. Zhao X, Li Y, Zhou Y. MicroRNA-96-3p promotes metastasis of papillary thyroid cancer through targeting SDHB. Cancer Cell Int 2019; 19:287.
119. van Horssen R, Ten Hagen TL, Eggermont AM. TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist 2006; 11:397-408.
120. Wu L, Pu X, Wang Q, Cao J, Xu F, Xu LI, et al. miR-96 induces cisplatin chemoresistance in non-small cell lung cancer cells by downregulating SAMD9. Oncol Lett 2016; 11:945-952.
121. Hall A. The cellular functions of small GTP-binding proteins. Science 1990; 249:635-640.
122. Campbell PM, Groehler AL, Lee KM, Ouellette MM, Khazak V, Der CJ. K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by Raf and phosphatidylinositol 3-kinase signaling. Cancer Res 2007; 67:2098-2106.
123. Kallifatidis G, Rausch V, Baumann B, Apel A, Beckermann BM, Groth A, et al. Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Gut 2009; 58:949-963.
124. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 2007; 1773:1263-1284.
125. Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res 2002; 12:9-18.
126. Yu S, Lu Z, Liu C, Meng Y, Ma Y, Zhao W, et al. miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. Cancer Res 2010; 70:6015-6025.
127. He RJ, Yu ZH, Zhang RY, Zhang ZY. Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacol Sin 2014; 35:1227-1246.
128. Su F, Ren F, Rong Y, Wang Y, Geng Y, Wang Y, et al. Protein tyrosine phosphatase Meg2 dephosphorylates signal transducer and activator of transcription 3 and suppresses tumor growth in breast cancer. Breast Cancer Res 2012; 14:R38.
129. Yuan T, Wang Y, Zhao ZJ, Gu H. Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. J Biol Chem 2010; 285:14861-14870.
130. Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, et al. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 2006; 12:11-19.
131. Turkson J, Jove R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 2000; 19:6613-6626.
132. Hong Y, Liang H, Uzair Ur R, Wang Y, Zhang W, Zhou Y, et al. miR-96 promotes cell proliferation, migration and invasion by targeting PTPN9 in breast cancer. Sci Rep 2016; 6:37421.
133. Ma X, Shi W, Peng L, Qin X, Hui Y. MiR-96 enhances cellular proliferation and tumorigenicity of human cervical carcinoma cells through PTPN9. Saudi J Biol Sci 2018; 25:863-867.
134. Suzuki A, Kusakai G, Kishimoto A, Lu J, Ogura T, Lavin MF, et al. Identification of a novel protein kinase mediating Akt survival signaling to the ATM protein. J Biol Chem 2003; 278:48-53.
135. Suzuki A, Kusakai G, Kishimoto A, Lu J, Ogura T, Esumi H. ARK5 suppresses the cell death induced by nutrient starvation and death receptors via inhibition of caspase 8 activation, but not by chemotherapeutic agents or UV irradiation. Oncogene 2003; 22:6177-6182.
136. Suzuki A, Kusakai G, Kishimoto A, Shimojo Y, Miyamoto S, Ogura T, et al. Regulation of caspase-6 and FLIP by the AMPK family member ARK5. Oncogene 2004; 23:7067-7075.
137. Huang X, Lv W, Zhang JH, Lu DL. miR96 functions as a tumor suppressor gene by targeting NUAK1 in pancreatic cancer. Int J Mol Med 2014; 34:1599-1605.
138. Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 2005; 5:172-183.
139. Huang T, Fu Y, Wang S, Xu M, Yin X, Zhou M, et al. miR-96 acts as a tumor suppressor via targeting the BCR-ABL1 oncogene in chronic myeloid leukemia blastic transformation. Biomed Pharmacother 2019; 119:109413.
140. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008; 358:1160-1174.
141. Tsai YC, Zeng T, Abou-Kheir W, Yeh HL, Yin JJ, Lee YC, et al. Disruption of ETV6 leads to TWIST1-dependent progression and resistance to epidermal growth factor receptor tyrosine kinase inhibitors in prostate cancer. Mol Cancer 2018; 17:42.
142. Li JJ, Liu DP, Liu GT, Xie D. EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor. Oncogene 2009; 28:1759-1768.
143. Wang TH, Yeh CT, Ho JY, Ng KF, Chen TC. OncomiR miR-96 and miR-182 promote cell proliferation and invasion through targeting ephrinA5 in hepatocellular carcinoma. Mol Carcinog 2016; 55:366-375.
144. Chiang CH, Hou MF, Hung WC. Up-regulation of miR-182 by beta-catenin in breast cancer increases tumorigenicity and invasiveness by targeting the matrix metalloproteinase inhibitor RECK. Biochim Biophys Acta 2013; 1830:3067-3076.
145. Hirata H, Ueno K, Shahryari V, Tanaka Y, Tabatabai ZL, Hinoda Y, et al. Oncogenic miRNA-182-5p targets Smad4 and RECK in human bladder cancer. PLoS One 2012; 7:e51056.
146. Zhao H, Wang Y, Yang L, Jiang R, Li W. MiR-25 promotes gastric cancer cells growth and motility by targeting RECK. Mol Cell Biochem 2014; 385:207-213.
147. Xia H, Chen S, Chen K, Huang H, Ma H. MiR-96 promotes proliferation and chemo- or radioresistance by down-regulating RECK in esophageal cancer. Biomed Pharmacother 2014; 68:951-958.
148. Zhang J, Kong X, Li J, Luo Q, Li X, Shen L, et al. miR-96 promotes tumor proliferation and invasion by targeting RECK in breast cancer. Oncol Rep 2014; 31:1357-1363.
149. Guo H, Li Q, Li W, Zheng T, Zhao S, Liu Z. MiR-96 downregulates RECK to promote growth and motility of non-small cell lung cancer cells. Mol Cell Biochem 2014; 390:155-160.
150. Iwai N, Yasui K, Tomie A, Gen Y, Terasaki K, Kitaichi T, et al. Oncogenic miR-96-5p inhibits apoptosis by targeting the caspase-9 gene in hepatocellular carcinoma. Int J Oncol 2018; 53:237-245.
151. Matsuhashi S, Manirujjaman M, Hamajima H, Ozaki I. Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions. Int J Mol Sci 2019; 20.
152. Guo P, Yu Y, Tian Z, Lin Y, Qiu Y, Yao W, et al. Upregulation of miR-96 promotes radioresistance in glioblastoma cells via targeting PDCD4. Int J Oncol 2018; 53:1591-1600.
153. Colhado Rodrigues BL, Lallo MA, Perez EC. The controversial role of autophagy in tumor development: A systematic review. Immunol Invest 2020; 49:386-396.
154. Guo F, Liu X, Cai H, Le W. Autophagy in neurodegenerative diseases: pathogenesis and therapy. Brain Pathol 2018; 28:3-13.
155. Han J, Hou W, Goldstein LA, Stolz DB, Watkins SC, Rabinowich H. A Complex between Atg7 and Caspase-9: A Novel mechanism of cross-regulation between autophagy and apoptosis. J Biol Chem 2014; 289:6485-6497.
156. Zheng W, Xie W, Yin D, Luo R, Liu M, Guo F. ATG5 and ATG7 induced autophagy interplays with UPR via PERK signaling. Cell Commun Signal 2019; 17:42.
157. Li JJ, Chen XF, Wang M, Zhang PP, Zhang F, Zhang JJ. Long non-coding RNA UCA1 promotes autophagy by targeting miR-96-5p in acute myeloid leukaemia. Clin Exp Pharmacol Physiol 2020; 47:877-885.
158. Bianco S, Jangal M, Garneau D, Gevry N. LRH-1 controls proliferation in breast tumor cells by regulating CDKN1A gene expression. Oncogene 2015; 34:4509-4518.
159. Wu Z, Liu K, Wang Y, Xu Z, Meng J, Gu S. Upregulation of microRNA-96 and its oncogenic functions by targeting CDKN1A in bladder cancer. Cancer Cell Int 2015; 15:107.