Abstract
The cellular signaling network plays a fundamental role during development and disease, especially cancer progression. By deregulating signaling pathways, cancer cells acquire hallmarks of the disease including uncontrolled proliferation, evasion from cell death, activation of angiogenesis, invasion, and metastasis. Noncoding RNAs make substantial contributions to regulating signal transduction in cancer, thereby promoting or suppressing different biological processes during tumorigenesis. This chapter provides an overview on the regulatory functions of noncoding RNAs in the signaling network in cancer cells. It summarizes examples of noncoding RNAs that act as oncogenes or tumor-suppressing genes involved in key signal pathways as well as signal crosstalk in cancer cells.
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References
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi:10.1016/j.cell.2011.02.013.
Gschwind A, Fischer OM, Ullrich A. Timeline-the discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer. 2004;4(5):361–70. doi:10.1038/nrc1360.
Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;366(1):2–16. doi:10.1016/j.gene.2005.10.018.
Webster RJ, Giles KM, Price KJ, et al. Regulation of epidermal growth factor receptor signaling in human cancer cells by microRNA-7. J Biol Chem. 2009;284(9):5731–41. doi:10.1074/jbc.M804280200.
Kefas B, Godlewski J, Comeau L, et al. MicroRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res. 2008;68(10):3566–72. doi:10.1158/0008-5472.Can-07-6639.
Garofalo M, Jeon YJ, Nuovo GJ, et al. MiR-34a/c-dependent PDGFR-alpha/beta down-regulation inhibits tumorigenesis and enhances TRAIL-induced apoptosis in lung cancer. PLoS ONE. 2013;8(6):e67581. doi:10.1371/journal.pone.0067581.
Migliore C, Petrelli A, Ghiso E, et al. MicroRNAs impair MET-mediated invasive growth. Cancer Res. 2008;68(24):10128–36. doi:10.1158/0008-5472.CAN-08-2148.
Peng Y, Guo JJ, Liu YM. Wu XL MicroRNA-34A inhibits the growth, invasion and metastasis of gastric cancer by targeting PDGFR and MET expression. Biosci Rep. 2014;34(3):247–56. doi:10.1042/BSR20140020.
Su J, Liang H, Yao W, et al. MiR-143 and MiR-145 regulate IGF1R to suppress cell proliferation in colorectal cancer. PLoS ONE. 2014;9(12):e114420. doi:10.1371/journal.pone.0114420.
Yan X, Chen X, Liang H, et al. MiR-143 and miR-145 synergistically regulate ERBB3 to suppress cell proliferation and invasion in breast cancer. Mol Cancer. 2014;13:220. doi:10.1186/1476-4598-13-220.
Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279–90. doi:10.1038/sj.onc.1210421.
Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3(1):11–22. doi:10.1038/nrc969.
Sayed D, Rane S, Lypowy J, et al. MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths. Mol Biol Cell. 2008;19(8):3272–82. doi:10.1091/mbc.E08-02-0159.
Hanafusa H, Torii S, Yasunaga T, Nishida E. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol. 2002;4(11):850–8. doi:10.1038/ncb867.
Liu M, Wu H, Liu T, et al. Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma. Cell Res. 2009;19(7):828–37. doi:10.1038/cr.2009.72.
Buganim Y, Solomon H, Rais Y, et al. p53 regulates the Ras circuit to inhibit the expression of a cancer-related gene signature by various molecular pathways. Cancer Res. 2010;70(6):2274–84. doi:10.1158/0008-5472.Can-09-2661.
Talotta F, Cimmino A, Matarazzo MR, et al. An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation. Oncogene. 2009;28(1):73–84. doi:10.1038/onc.2008.370.
Lu Z, Liu M, Stribinskis V, et al. MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene. 2008;27(31):4373–9. doi:10.1038/onc.2008.72.
Hatley ME, Patrick DM, Garcia MR, et al. Modulation of K-Ras-dependent lung tumorigenesis by microRNA-21. Cancer Cell. 2010;18(3):282–93. doi:10.1016/j.ccr.2010.08.013.
Lenarduzzi M, Hui ABY, Alajez NM et al. MicroRNA-193b enhances tumor progression via down regulation of neurofibromin 1. Plos ONE. 2013;8(1). doi:ARTN e53765.
Garcia-Orti L, Cristobal I, Cirauqui C et al. Integration of SNP and mRNA arrays with microRNA profiling reveals that miR-370 is up-regulated and targets NF1 in acute myeloid leukemia. Plos ONE. 2012;7(10). doi:ARTN e47717.
Lv ZH, Yang LZ. MiR-124 inhibits the growth of glioblastoma through the down-regulation of SOS1. Mol Med Rep. 2013;8(2):345–9. doi:10.3892/mmr.2013.1561.
Singh A, Greninger P, Rhodes D, et al. A gene expression signature associated with “K-Ras Addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009;15(6):489–500. doi:10.1016/j.ccr.2009.03.022.
Wagner PL, Stiedl AC, Wilbertz T, et al. Frequency and clinicopathologic correlates of KRAS amplification in non-small cell lung carcinoma. Lung Cancer. 2011;74(1):118–23. doi:10.1016/j.lungcan.2011.01.029.
Mita H, Toyota M, Aoki F et al. A novel method, digital genome scanning detects KRAS gene amplification in gastric cancers: involvement of overexpressed wild-type KRAS in downstream signaling and cancer cell growth. BMC Cancer. 2009;9. doi:Artn 198.
Johnson SM, Grosshans H, Shingara J, et al. RAS is regulated by the let-7 MicroRNA family. Cell. 2005;120(5):635–47. doi:10.1016/j.cell.2005.01.014.
Akao Y, Nakagawa Y, Naoe T. Let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol Pharm Bull. 2006;29(5):903–6. doi:10.1248/bpb.29.903.
Yu F, Yao H, Zhu PC, et al. Let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007;131(6):1109–23. doi:10.1016/j.cell.2007.10.054.
Kumar MS, Erkeland SJ, Pester RE, et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci U S A. 2008;105(10):3903–8. doi:10.1073/pnas.0712321105.
Chin LJ, Ratner E, Leng SG, et al. A SNP in a let-7 microRNA complementary site in the KRAS 3’ untranslated region increases non-small cell lung cancer risk. Cancer Res. 2008;68(20):8535–40. doi:10.1158/0008-5472.Can-08-2129.
Poliseno L, Salmena L, Zhang JW, et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010;465(7301):1033–8. doi:10.1038/nature09144.
Liu SM, Lu J, Lee HC, et al. MiR-524-5p suppresses the growth of oncogenic BRAF melanoma by targeting BRAF and ERK2. Oncotarget. 2014;5(19):9444–59.
Liu Z, Jiang Z, Huang J, et al. MiR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways. Int J Oncol. 2014;44(5):1571–80. doi:10.3892/ijo.2014.2322.
Glover AR, Zhao JT, Gill AJ et al. MicroRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma. Oncotarget. 2015; doi:10.18632/oncotarget.5383.
Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501. doi:10.1038/nrc839.
Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006;441(7092):424–30. doi:10.1038/nature04869.
Guo CG, Sah JF, Beard L, et al. The non-coding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers. Gene Chromosomes Cancer. 2008;47(11):939–46. doi:10.1002/gcc.20596.
Fang Y, Xue JL, Shen Q, et al. MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. Hepatology. 2012;55(6):1852–62. doi:10.1002/hep.25576.
Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27(41):5497–510. doi:10.1038/onc.2008.245.
Alimonti A, Carracedo A, Clohessy JG, et al. Subtle variations in Pten dose determine cancer susceptibility. Nat Genet. 2010;42(5):454–8. doi:10.1038/ng.556.
Meng FY, Henson R, Wehbe-Janek H, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133(2):647–58. doi:10.1053/j.gastro.2007.05.022.
Yang H, Kong W, He L, et al. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res. 2008;68(2):425–33. doi:10.1158/0008-5472.Can-07-2488.
Garofalo M, Di Leva G, Romano G, et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 down-regulation. Cancer Cell. 2009;16(6):498–509. doi:10.1016/j.ccr.2009.10.014.
Tay Y, Kats L, Salmena L, et al. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell. 2011;147(2):344–57. doi:10.1016/j.cell.2011.09.029.
Karreth FA, Tay Y, Pema D et al. In vivo identification of tumor-suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell. 2011;147(4):948–948. doi:10.1016/j.cell.2011.10.032.
Johnsson P, Ackley A, Vidarsdottir L, et al. A pseudogene long-non-coding-RNA network regulates PTEN transcription and translation in human cells. Nat Struct Mol Biol. 2013;20(4):440–6. doi:10.1038/nsmb.2516.
Brognard J, Sierecki E, Gao TY, Newton AC. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell. 2007;25(6):917–31. doi:10.1016/j.molcel.2007.02.017.
Tsukamoto Y, Nakada C, Noguchi T, et al. MicroRNA-375 is down-regulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3 zeta. Cancer Res. 2010;70(6):2339–49. doi:10.1158/0008-5472.Can-09-2777.
Foley NH, Bray IM, Tivnan A et al. MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2. Mol Cancer. 2010;9. doi:Artn 83.
Uesugi A, Kozaki K, Tsuruta T, et al. The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer. Cancer Res. 2011;71(17):5765–78. doi:10.1158/0008-5472.Can-11-0368.
Cai JC, Fang LS, Huang YB, et al. MiR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer. Cancer Res. 2013;73(17):5402–15. doi:10.1158/0008-5472.Can-13-0297.
Massague J. TGFbeta in cancer. Cell. 2008;134(2):215–30. doi:10.1016/j.cell.2008.07.001.
Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer. 2010;10(6):415–24. doi:10.1038/nrc2853.
Mestdagh P, Bostrom AK, Impens F, et al. The miR-17-92 microRNA cluster regulates multiple components of the TGF-beta pathway in neuroblastoma. Mol Cell. 2010;40(5):762–73. doi:10.1016/j.molcel.2010.11.038.
Smith AL, Iwanaga R, Drasin DJ, et al. The miR-106b-25 cluster targets Smad7, activates TGF-beta signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer. Oncogene. 2012;31(50):5162–71. doi:10.1038/onc.2012.11.
Petrocca F, Visone R, Onelli MR, et al. E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell. 2008;13(3):272–86. doi:10.1016/j.ccr.2008.02.013.
Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593–601. doi:10.1038/ncb1722.
Bracken CP, Gregory PA, Kolesnikoff N, et al. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 2008;68(19):7846–54. doi:10.1158/0008-5472.Can-08-1942.
Yuan JH, Yang F, Wang F, et al. A long non-coding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25(5):666–81. doi:10.1016/j.ccr.2014.03.010.
Davis BN, Hilyard AC, Lagna G, Hata A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature. 2008;454(7200):56–61. doi:10.1038/nature07086.
Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8(5):387–98. doi:10.1038/nrc2389.
Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149(6):1192–205. doi:10.1016/j.cell.2012.05.012.
Kim NH, Kim HS, Kim NG et al. p53 and microRNA-34 are suppressors of canonical Wnt signaling. Sci Signal. 2011;4(197). doi:ARTN ra71.
Kim NH, Cha YH, Kang SE, et al. P53 regulates nuclear GSK-3 levels through miR-34-mediated Axin2 suppression in colorectal cancer cells. Cell Cycle. 2013;12(10):1578–87. doi:10.4161/cc.24739.
Zhang Y, Wei W, Cheng N, et al. Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling. Hepatology. 2012;56(5):1631–40. doi:10.1002/hep.25849.
Shen G, Jia H, Tai Q, et al. MiR-106b down-regulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. Carcinogenesis. 2013;34(1):211–9. doi:10.1093/carcin/bgs320.
Li Q, Shen K, Zhao Y, et al. MicroRNA-222 promotes tumorigenesis via targeting DKK2 and activating the Wnt/beta-catenin signaling pathway. FEBS Lett. 2013;587(12):1742–8. doi:10.1016/j.febslet.2013.04.002.
Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer. 2003;3(10):756–67. doi:10.1038/nrc1186.
Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678–89. doi:10.1038/nrm2009.
Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216–33. doi:10.1016/j.cell.2009.03.045.
Ji Q, Hao X, Meng Y, et al. Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer. 2008;8:266. doi:10.1186/1471-2407-8-266.
Li YQ, Guessous F, Zhang Y, et al. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res. 2009;69(19):7569–76. doi:10.1158/0008-5472.Can-09-0529.
Ji Q, Hao X, Zhang M, et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS ONE. 2009;4(8):e6816. doi:10.1371/journal.pone.0006816.
de Antonellis P, Medaglia C, Cusanelli E, et al. MiR-34a targeting of Notch ligand delta-like 1 impairs CD15+/CD133+ tumor-propagating cells and supports neural differentiation in medulloblastoma. PLoS ONE. 2011;6(9):e24584. doi:10.1371/journal.pone.0024584.
Bu PC, Chen KY, Chen JH, et al. A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. Cell Stem Cell. 2013;12(5):602–15. doi:10.1016/j.stem.2013.03.002.
Forloni M, Dogra SK, Dong Y, et al. MiR-146a promotes the initiation and progression of melanoma by activating Notch signaling. Elife. 2014;3:e01460. doi:10.7554/eLife.01460.
Rubin LL, de Sauvage FJ. Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov. 2006;5(12):1026–33. doi:10.1038/nrd2086.
Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell. 2008;15(6):801–12. doi:10.1016/j.devcel.2008.11.010.
Merchant AA, Matsui W. Targeting Hedgehog-a cancer stem cell pathway. Clin Cancer Res. 2010;16(12):3130–40. doi:10.1158/1078-0432.CCR-09-2846.
Ferretti E, De Smaele E, Miele E, et al. Concerted microRNA control of Hedgehog signalling in cerebellar neuronal progenitor and tumour cells. EMBO J. 2008;27(19):2616–27. doi:10.1038/emboj.2008.172.
Lee DY, Deng ZQ, Wang CH, Yang BB. MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc Natl Acad Sci U S A. 2007;104(51):20350–5. doi:10.1073/pnas.0706901104.
Li Y, Zhang DQ, Chen CW, et al. MicroRNA-212 displays tumor-promoting properties in non-small cell lung cancer cells and targets the hedgehog pathway receptor PTCH1. Mol Biol Cell. 2012;23(8):1423–34. doi:10.1091/mbc.E11-09-0777.
Pan DJ. The Hippo signaling pathway in development and cancer. Dev Cell. 2010;19(4):491–505. doi:10.1016/j.devcel.2010.09.011.
Harvey KF, Zhang XM, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13(4):246–57. doi:10.1038/nrc3458.
Lin CW, Chang YL, Chang YC et al. MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1. Nat Commun 2013;4. doi:ARTN 1877.
Liu AM, Poon RTP, Luk JM. MicroRNA-375 targets Hippo-signaling effector YAP in liver cancer and inhibits tumor properties. Biochem Bioph Res Commun. 2010;394(3):623–7. doi:10.1016/j.bbrc.2010.03.036.
Mori M, Triboulet R, Mohseni M, et al. Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer. Cell. 2014;156(5):893–906. doi:10.1016/j.cell.2013.12.043.
Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9(11):798–809. doi:10.1038/nrc2734.
Jiang SA, Zhang HW, Lu MH, et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 2010;70(8):3119–27. doi:10.1158/0008-5472.Can-09-4250.
Wu H, Huang M, Cao P, et al. MiR-135a targets JAK2 and inhibits gastric cancer cell proliferation. Cancer Biol Ther. 2012;13(5):281–8. doi:10.4161/cbt.13.5.18943.
Hirata H, Hinoda Y, Ueno K, et al. MicroRNA-1826 targets VEGFC, beta-catenin (CTNNB1) and MEK1 (MAP2K1) in human bladder cancer. Carcinogenesis. 2012;33(1):41–8. doi:10.1093/carcin/bgr239.
Ueno K, Hirata H, Shahryari V, et al. microRNA-183 is an oncogene targeting Dkk-3 and SMAD4 in prostate cancer. Brit J Cancer. 2013;108(8):1659–67. doi:10.1038/bjc.2013.125.
Wu K, Ding J, Chen C, et al. Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development. Hepatology. 2012;56(6):2255–67. doi:10.1002/hep.26007.
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Hu, J., Markowitz, G.J., Wang, X. (2016). Noncoding RNAs Regulating Cancer Signaling Network. In: Song, E. (eds) The Long and Short Non-coding RNAs in Cancer Biology. Advances in Experimental Medicine and Biology, vol 927. Springer, Singapore. https://doi.org/10.1007/978-981-10-1498-7_11
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