Abstract
Clinical intervention for patients with advanced prostate cancer (PCa) remains challenging due to the inevitable recurrence of castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT). Cancer stem cells (CSCs) with serial tumor-propagating capacity are considered to be the driving force for PCa progression and recurrence. In this study, we report that the miR-302/367 cluster, a previously identified potent pluripotency regulator, is upregulated in prostate tumors. Specifically, the forced expression of the miR-302/367 cluster accelerates the in vitro and in vivo growth of PCa cells and their resistance to androgen ablation, whereas the knockdown of the miR-302/367 cluster using anti-sense RNA suppresses the incidence of formation, growth rate and endpoint weight of PCa cell tumors. Mechanistically, we find that LATS2, a key component of the tumor-suppressive Hippo signaling pathway, acts as a direct target of the miR-302/367 cluster in PCa cells. The downregulation of LATS2 by the miR-302/367 cluster reduces the phosphorylation and enhances the nuclear translocation of the YAP oncoprotein. Conversely, the restoration of LATS2 expression abrogates the tumor-promoting effects of forced miR-302/367 cluster expression. Collectively, the potent pluripotency regulator-triggered miR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes castration resistance. Thus, targeting this signaling axis may represent a promising therapeutic strategy for CRPC.
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References
Torre LA, Sauer AM, Chen MS Jr, Kagawa-Singer M, Jemal A, Siegel RL . Cancer statistics for Asian Americans, Native Hawaiians, and Pacific Islanders, 2016: Converging incidence in males and females. CA Cancer J Clin 2016; 66: 182–202.
Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360: 103–106.
Harris WP, Mostaghel EA, Nelson PS, Montgomery B . Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol 2009; 6: 76–85.
Heinlein CA, Chang C . Androgen receptor in prostate cancer. Endocrine Rev 2004; 25: 276–308.
Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, Castillo-Martin M, Quinn SA, Rodriguez-Barrueco R et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell 2012; 22: 373–388.
Fong CY, Gilan O, Lam EY, Rubin AF, Ftouni S, Tyler D et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature 2015; 525: 538–542.
Qin J, Liu X, Laffin B, Chen X, Choy G, Jeter CR et al. The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell 2012; 10: 556–569.
Boumahdi S, Driessens G, Lapouge G, Rorive S, Nassar D, Le Mercier M et al. SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature 2014; 511: 246–250.
Badcock G, Pigott C, Goepel J, Andrews PW . The human embryonal carcinoma marker antigen TRA-1-60 is a sialylated keratan sulfate proteoglycan. Cancer Res 1999; 59: 4715–4719.
Rajasekhar VK, Studer L, Gerald W, Socci ND, Scher HI . Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-kappaB signalling. Nat Commun 2011; 2: 162.
Houbaviy HB, Murray MF, Sharp PA . Embryonic stem cell-specific MicroRNAs. Dev Cell 2003; 5: 351–358.
Lu Y, Loh YH, Li H, Cesana M, Ficarro SB, Parikh JR et al. Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells. Cell Stem Cell 2014; 15: 92–101.
Yu FX, Guan KL . The Hippo pathway: regulators and regulations. Genes Dev 2013; 27: 355–371.
Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 2007; 21: 2747–2761.
Sebio A, Lenz HJ . Molecular pathways: Hippo signaling, a critical tumor suppressor. Clin Cancer Res 2015; 21: 5002–5007.
Hong AW, Meng Z, Guan KL . The Hippo pathway in intestinal regeneration and disease. Nat Rev Gastroenterol Hepatol 2016; 13: 324–337.
Harvey K, Tapon N . The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network. Nat Rev Cancer 2007; 7: 182–191.
Eisinger-Mathason TS, Mucaj V, Biju KM, Nakazawa MS, Gohil M, Cash TP et al. Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis. Proc Natl Acad Sci USA 2015; 112: E3402–E3411.
Kim T, Yang SJ, Hwang D, Song J, Kim M, Kyum Kim S et al. A basal-like breast cancer-specific role for SRF-IL6 in YAP-induced cancer stemness. Nat Commun 2015; 6: 10186.
Hayashi H, Higashi T, Yokoyama N, Kaida T, Sakamoto K, Fukushima Y et al. An imbalance in TAZ and YAP expression in hepatocellular carcinoma confers cancer stem cell-like behaviors contributing to disease progression. Cancer Res 2015; 75: 4985–4997.
Touil Y, Igoudjil W, Corvaisier M, Dessein AF, Vandomme J, Monte D et al. Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis. Clin Cancer Res 2014; 20: 837–846.
Mao X, Yu Y, Boyd LK, Ren G, Lin D, Chaplin T et al. Distinct genomic alterations in prostate cancers in Chinese and Western populations suggest alternative pathways of prostate carcinogenesis. Cancer Res 2010; 70: 5207–5212.
Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Sidransky D et al. Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res 1998; 58: 204–209.
Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 2003; 4: 209–221.
Medema RH, Kops GJ, Bos JL, Burgering BM . AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 2000; 404: 782–787.
Zlotorynski E . Tumour suppressors: the dark side of p21. Nat Rev Cancer 2016; 16: 481.
Grogan TM, Lippman SM, Spier CM, Slymen DJ, Rybski JA, Rangel CS et al. Independent prognostic significance of a nuclear proliferation antigen in diffuse large cell lymphomas as determined by the monoclonal antibody Ki-67. Blood 1988; 71: 1157–1160.
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H . Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 1984; 133: 1710–1715.
Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004; 10: 33–39.
Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R et al. Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin Cancer Res 2015; 21: 1273–1280.
Jiao J, Wang S, Qiao R, Vivanco I, Watson PA, Sawyers CL et al. Murine cell lines derived from Pten null prostate cancer show the critical role of PTEN in hormone refractory prostate cancer development. Cancer Res 2007; 67: 6083–6091.
Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G et al. Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci Res 2006; 56: 450–458.
Li W, Wang L, Katoh H, Liu R, Zheng P, Liu Y . Identification of a tumor suppressor relay between the FOXP3 and the Hippo pathways in breast and prostate cancers. Cancer Res 2011; 71: 2162–2171.
Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T, Tamaki Y et al. Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin Cancer Res 2005; 11: 1380–1385.
Fang YX, Zhang XB, Wei W, Liu YW, Chen JZ, Xue JL et al. Development of chimeric gene regulators for cancer-specific gene therapy with both transcriptional and translational targeting. Mol Biotechnol 2010; 45: 71–81.
Mo JS, Park HW, Guan KL . The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep 2014; 15: 642–656.
Zhao B, Li L, Lei Q, Guan KL . The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev 2010; 24: 862–874.
Chen L, Heikkinen L, Emily Knott K, Liang Y, Wong G . Evolutionary conservation and function of the human embryonic stem cell specific miR-302/367 cluster. Comp Biochem Physiol Part D Genomics Proteomics 2015; 16: 83–98.
Anokye-Danso F, Trivedi CM, Juhr D, Gupta M, Cui Z, Tian Y et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 2011; 8: 376–388.
Wang Y, Zhao L, Xiao Q, Jiang L, He M, Bai X et al. miR-302a/b/c/d cooperatively inhibit BCRP expression to increase drug sensitivity in breast cancer cells. Gynecol Oncol 2016; 141: 592–601.
Zhao L, Wang Y, Jiang L, He M, Bai X, Yu L et al. MiR-302a/b/c/d cooperatively sensitizes breast cancer cells to adriamycin via suppressing P-glycoprotein(P-gp) by targeting MAP/ERK kinase kinase 1 (MEKK1). J Exp Clin Cancer Res 2016; 35: 25.
Tian Y, Zhang Y, Hurd L, Hannenhalli S, Liu F, Lu MM et al. Regulation of lung endoderm progenitor cell behavior by miR302/367. Development 2011; 138: 1235–1245.
Nguyen LT, Tretiakova MS, Silvis MR, Lucas J, Klezovitch O, Coleman I et al. ERG activates the YAP1 transcriptional program and induces the development of age-related prostate tumors. Cancer Cell 2015; 27: 797–808.
Dai JL, Maiorino CA, Gkonos PJ, Burnstein KL . Androgenic up-regulation of androgen receptor cDNA expression in androgen-independent prostate cancer cells. Steroids 1996; 61: 531–539.
Zhang K, Zhao H, Ji Z, Zhang C, Zhou P, Wang L et al. Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition. Oncogene 2016; 35: 1271–1282.
Haraguchi T, Ozaki Y, Iba H . Vectors expressing efficient RNA decoys achieve the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res 2009; 37: e43.
Matsuyama H, Suzuki HI, Nishimori H, Noguchi M, Yao T, Komatsu N et al. miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma. Blood 2011; 118: 6881–6892.
Chu M, Chang Y, Guo Y, Wang N, Cui J, Gao WQ . Regulation and methylation of tumor suppressor miR-124 by androgen receptor in prostate cancer cells. PLoS One 2015; 10: e0116197.
Acknowledgements
The study is supported by grants from the Chinese Ministry of Science and Technology (2017YFA0102900), the National Natural Science Foundation of China (81372189 and 81630073), the Science and Technology Commission of Shanghai Municipality (16JC1405700), the KC Wong foundation, and the Shanghai Eastern Hospital Stem Cell Research Base Fund to Wei-Qiang Gao, and Helen He Zhu received support from the State Key Laboratory of Oncogenes and Related Genes (90-16-03), Shanghai Rising-Star Program (17QA1402100), Shanghai Institutions of Higher Learning (The Program for Professor of Special Appointment (Young Eastern Scholar) QD2015002), School of Medicine at Shanghai Jiao Tong University (Excellent Youth Scholar Initiation Grant 16XJ11003) and Ren Ji Hospital (Seed Project RJZZ14-010).
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Guo, Y., Cui, J., Ji, Z. et al. miR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes the development of castration resistance. Oncogene 36, 6336–6347 (2017). https://doi.org/10.1038/onc.2017.240
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DOI: https://doi.org/10.1038/onc.2017.240
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