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Current Pharmaceutical Biotechnology

Author(s): Lifang Hao, Hui Li*, Su Zhang, Yanlei Yang, Zhenzhen Xu, Yanfen Zhang and Zhongcheng Liu*

DOI: 10.2174/1389201019666191003142119

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Integrative Exome Sequencing Analysis in Castration-Resistant Prostate Cancer in Chinese Population

Page: [140 - 148] Pages: 9

  • * (Excluding Mailing and Handling)

Abstract

Background: Castration-resistant Prostate Cancer (CRPC) is a fatal disease with rapid growth. The malignancy usually presents with metastasis and poor prognosis, and causes 100% mortality. Therefore, the treatment of CRPC is extremely challenging, and its pathogenesis need to be elucidated urgently.

Objective: The high throughput sequencing technology was used to sequence the whole exome associated with CRPC, to explore the molecular mechanism of CRPC, and to find the potential therapeutic targets.

Methods: We performed whole-exome sequencing of FFPE tissue from 11 Chinese adult male patients. Genomic DNA was fragmented and enriched for whole-exome sequencing using the QiAamp DNA FFPE Tissue KIT, sequenced on an Illumina HiSeq2000 platform, and the relevant genes were analyzed using biological information. Finally, immunohistochemistry method was used to detect the phosphorylation level of LATS1 in CRPC tissues of MST1 mutant and non-mutant patients.

Results: We have screened 85 significant mutant genes with relatively high mutation rates of TP53, AR, KMT2, DMAPK1, PIK3R1, SH2B3, WHSC1, KMT2D, MST1 and MAPK1. We first found that MST1 has multiple mutations in CRPC patients, and the MST1 plays an important role in the Hippo pathway. Immunohistochemistry results showed that the phosphorylation level of LATS1 in the mutant patients was significantly lower than that in the non-mutant patients.

Conclusion: We speculate that MST1 would be a new potential target for the treatment of CRPC by regulating Hippo signaling pathway. The results provided an important clue to the molecular mechanism of CRPC.

Keywords: CRPC, MST1 mutation, whole-exome sequencing, bioinformatics analysis, Hippo signaling pathway, LATS1.

Graphical Abstract

[1]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[2]
Grasso, C.S.; Wu, Y.M.; Robinson, D.R.; Cao, X.; Dhanasekaran, S.M.; Khan, A.P.; Quist, M.J.; Jing, X.; Lonigro, R.J.; Brenner, J.C.; Asangani, I.A.; Ateeq, B.; Chun, S.Y.; Siddiqui, J.; Sam, L.; Anstett, M.; Mehra, R.; Prensner, J.R.; Palanisamy, N.; Ryslik, G.A.; Vandin, F.; Raphael, B.J.; Kunju, L.P.; Rhodes, D.R.; Pienta, K.J.; Chinnaiyan, A.M.; Tomlins, S.A. The mutational landscape of lethal castration-resistant prostate cancer. Nature, 2012, 487(7406), 239-243.
[http://dx.doi.org/10.1038/nature11125] [PMID: 22722839]
[3]
Barry, M.J.; Simmons, L.H. Prevention of prostate cancer morbidity and mortality: Primary prevention and early detection. Med. Clin. North Am., 2017, 101(4), 787-806.
[http://dx.doi.org/10.1016/j.mcna.2017.03.009] [PMID: 28577627]
[4]
Harris, W.P.; Mostaghel, E.A.; Nelson, P.S.; Montgomery, B. Androgen deprivation therapy: Progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat. Clin. Pract. Urol., 2009, 6(2), 76-85.
[http://dx.doi.org/10.1038/ncpuro1296] [PMID: 19198621]
[5]
Amaral, T.M.; Macedo, D.; Fernandes, I.; Costa, L. Castration-resistant prostate cancer: Mechanisms, targets, and treatment. Prostate Cancer, 2012, 2012(7)327253
[http://dx.doi.org/10.1155/2012/327253] [PMID: 22530130]
[6]
Tolkach, Y.; Niehoff, E.M.; Stahl, A.F.; Zhao, C.; Kristiansen, G.; Müller, S.C.; Ellinger, J. YRNA expression in prostate cancer patients: diagnostic and prognostic implications. World J. Urol., 2018, 36(7), 1073-1078.
[http://dx.doi.org/10.1007/s00345-018-2250-6] [PMID: 29492585]
[7]
Lescarbeau, R.M.; Kaplan, D.L. Quantitative analysis of castration resistant prostate cancer progression through phosphoproteome signaling. BMC Cancer, 2014, 14, 325.
[http://dx.doi.org/10.1186/1471-2407-14-325] [PMID: 24885093]
[8]
Schalken, J.; Fitzpatrick, J.M. Enzalutamide: Targeting the androgen signalling pathway in metastatic castration-resistant prostate cancer. BJU Int., 2016, 117(2), 215-225.
[http://dx.doi.org/10.1111/bju.13123] [PMID: 25818596]
[9]
Ito, S.; Ueda, T.; Ueno, A.; Nakagawa, H.; Taniguchi, H.; Kayukawa, N.; Miki, T. A genetic screen in Drosophila for regulators of human prostate cancer progression. Biochem. Biophys. Res. Commun., 2014, 451(4), 548-555.
[http://dx.doi.org/10.1016/j.bbrc.2014.08.015] [PMID: 25117438]
[10]
Waltering, K.K.; Urbanucci, A.; Visakorpi, T. Androgen receptor (AR) aberrations in castration-resistant prostate cancer. Mol. Cell. Endocrinol., 2012, 360(1-2), 38-43.
[http://dx.doi.org/10.1016/j.mce.2011.12.019] [PMID: 22245783]
[11]
Bismar, T.A.; Yoshimoto, M.; Duan, Q.; Liu, S.; Sircar, K.; Squire, J.A. Interactions and relationships of PTEN, ERG, SPINK1 and AR in castration-resistant prostate cancer. Histopathology, 2012, 60(4), 645-652.
[http://dx.doi.org/10.1111/j.1365-2559.2011.04116.x] [PMID: 22260502]
[12]
Sharma, N.L.; Massie, C.E.; Ramos-Montoya, A.; Zecchini, V.; Scott, H.E.; Lamb, A.D.; MacArthur, S.; Stark, R.; Warren, A.Y.; Mills, I.G.; Neal, D.E. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell, 2013, 23(1), 35-47.
[http://dx.doi.org/10.1016/j.ccr.2012.11.010] [PMID: 23260764]
[13]
Azad, A.A.; Volik, S.V.; Wyatt, A.W.; Haegert, A.; Le Bihan, S.; Bell, R.H.; Anderson, S.A.; McConeghy, B.; Shukin, R.; Bazov, J.; Youngren, J.; Paris, P.; Thomas, G.; Small, E.J.; Wang, Y.; Gleave, M.E.; Collins, C.C.; Chi, K.N. Androgen receptor gene aberrations in circulating cell-free DNA: Biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin. Cancer Res., 2015, 21(10), 2315-2324.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2666] [PMID: 25712683]
[14]
Romanel, A.; Gasi Tandefelt, D.; Conteduca, V.; Jayaram, A.; Casiraghi, N.; Wetterskog, D.; Salvi, S.; Amadori, D.; Zafeiriou, Z.; Rescigno, P.; Bianchini, D.; Gurioli, G.; Casadio, V.; Carreira, S.; Goodall, J.; Wingate, A.; Ferraldeschi, R.; Tunariu, N.; Flohr, P.; De Giorgi, U.; de Bono, J.S.; Demichelis, F.; Attard, G. Plasma AR and abiraterone-resistant prostate cancer. Sci. Transl. Med., 2015, 7(312)312re10
[http://dx.doi.org/10.1126/scitranslmed.aac9511] [PMID: 26537258]
[15]
Robinson, D.; Van Allen, E.M.; Wu, Y.M.; Schultz, N.; Lonigro, R.J.; Mosquera, J.M.; Montgomery, B.; Taplin, M.E.; Pritchard, C.C.; Attard, G.; Beltran, H.; Abida, W.; Bradley, R.K.; Vinson, J.; Cao, X.; Vats, P.; Kunju, L.P.; Hussain, M.; Feng, F.Y.; Tomlins, S.A.; Cooney, K.A.; Smith, D.C.; Brennan, C.; Siddiqui, J.; Mehra, R.; Chen, Y.; Rathkopf, D.E.; Morris, M.J.; Solomon, S.B.; Durack, J.C.; Reuter, V.E.; Gopalan, A.; Gao, J.; Loda, M.; Lis, R.T.; Bowden, M.; Balk, S.P.; Gaviola, G.; Sougnez, C.; Gupta, M.; Yu, E.Y.; Mostaghel, E.A.; Cheng, H.H.; Mulcahy, H.; True, L.D.; Plymate, S.R.; Dvinge, H.; Ferraldeschi, R.; Flohr, P.; Miranda, S.; Zafeiriou, Z.; Tunariu, N.; Mateo, J.; Perez-Lopez, R.; Demichelis, F.; Robinson, B.D.; Schiffman, M.; Nanus, D.M.; Tagawa, S.T.; Sigaras, A.; Eng, K.W.; Elemento, O.; Sboner, A.; Heath, E.I.; Scher, H.I.; Pienta, K.J.; Kantoff, P.; de Bono, J.S.; Rubin, M.A.; Nelson, P.S.; Garraway, L.A.; Sawyers, C.L.; Chinnaiyan, A.M. Integrative clinical genomics of advanced prostate cancer. Cell, 2015, 161(5), 1215-1228.
[http://dx.doi.org/10.1016/j.cell.2015.05.001] [PMID: 26000489]
[16]
Armstrong, C.M.; Gao, A.C. CCN3-EZH2-AR feedback loop: New targets for enzalutamide and castration resistant prostate cancer. J. Cell Commun. Signal., 2017, 11(1), 89-91.
[http://dx.doi.org/10.1007/s12079-017-0378-6] [PMID: 28255661]
[17]
Wu, C.; Jin, X.; Yang, J.; Yang, Y.; He, Y.; Ding, L.; Pan, Y.; Chen, S.; Jiang, J.; Huang, H. Inhibition of EZH2 by chemo- and radiotherapy agents and small molecule inhibitors induces cell death in castration-resistant prostate cancer. Oncotarget, 2016, 7(3), 3440-3452.
[http://dx.doi.org/10.18632/oncotarget.6497] [PMID: 26657505]
[18]
Gu, P.; Chen, X.; Xie, R.; Han, J.; Xie, W.; Wang, B.; Dong, W.; Chen, C.; Yang, M.; Jiang, J.; Chen, Z.; Huang, J.; Lin, T. lncRNA HOXD-AS1 regulates proliferation and chemo-resistance of castration-resistant prostate cancer via recruiting WDR5. Mol. Ther., 2017, 25(8), 1959-1973.
[http://dx.doi.org/10.1016/j.ymthe.2017.04.016] [PMID: 28487115]
[19]
Menon, R.; Deng, M.; Rüenauver, K.; Queisser, A.; Peifer, M.; Offermann, A.; Boehm, D.; Vogel, W.; Scheble, V.; Fend, F.; Kristiansen, G.; Wernert, N.; Oberbeckmann, N.; Biskup, S.; Rubin, M.A.; Shaikhibrahim, Z.; Perner, S. Somatic copy number alterations by whole-exome sequencing implicates YWHAZ and PTK2 in castration-resistant prostate cancer. J. Pathol., 2013, 231(4), 505-516.
[http://dx.doi.org/10.1002/path.4274] [PMID: 24114522]
[20]
Xu, G.; Wu, J.; Zhou, L.; Chen, B.; Sun, Z.; Zhao, F.; Tao, Z. Characterization of the small RNA transcriptomes of androgen dependent and independent prostate cancer cell line by deep sequencing. PLoS One, 2010, 5(11)e15519
[http://dx.doi.org/10.1371/journal.pone.0015519] [PMID: 21152091]
[21]
Wei, Q.; Li, M.; Fu, X.; Tang, R.; Na, Y.; Jiang, M.; Li, Y. Global analysis of differentially expressed genes in androgen-independent prostate cancer. Prostate Cancer Prostatic Dis., 2007, 10(2), 167-174.
[http://dx.doi.org/10.1038/sj.pcan.4500933] [PMID: 17199135]
[22]
Isharwal, S.; Miller, M.C.; Epstein, J.I.; Mangold, L.A.; Humphreys, E.; Partin, A.W.; Veltri, R.W. Prognostic value of Her-2/neu and DNA index for progression, metastasis and prostate cancer-specific death in men with long-term follow-up after radical prostatectomy. Int. J. Cancer, 2008, 123(11), 2636-2643.
[http://dx.doi.org/10.1002/ijc.23838] [PMID: 18767043]
[23]
Baca, S.C.; Prandi, D.; Lawrence, M.S.; Mosquera, J.M.; Romanel, A.; Drier, Y.; Park, K.; Kitabayashi, N.; MacDonald, T.Y.; Ghandi, M. Van. Allen. E.; Kryukov, G.V.; Sboner, A.; Theurillat, J.P.; Soong, T.D.; Nickerson, E.; Auclair, D.; Tewari, A.; Beltran, H.; Onofrio, R.C.; Boysen, G.; Guiducci, C.; Barbieri, C.E.; Cibulskis, K.; Sivachenko, A.; Carter, S.L.; Saksena, G.; Voet, D.; Ramos, A.H.; Winckler, W.; Cipicchio, M.; Ardlie, K.; Kantoff, P.W.; Berger, M.F.; Gabriel, S.B.; Golub, T.R.; Meyerson, M.; Lander, E.S.; Elemento, O.; Getz, G.; Demichelis, F.; Rubin, M.A.; Garraway, L.A. Punctuated evolution of prostate cancer genomes. Cell, 2013, 153(3), 666-677.
[PMID: 23622249]
[24]
Holcomb, I.N.; Grove, D.I.; Kinnunen, M.; Friedman, C.L.; Gallaher, I.S.; Morgan, T.M.; Sather, C.L.; Delrow, J.J.; Nelson, P.S.; Lange, P.H.; Ellis, W.J.; True, L.D.; Young, J.M.; Hsu, L.; Trask, B.J.; Vessella, R.L. Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate cancer patients. Cancer Res., 2008, 68(14), 5599-5608.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-0812] [PMID: 18632612]
[25]
Huang, Y.; Jiang, X.; Liang, X.; Jiang, G. Molecular and cellular mechanisms of castration resistant prostate cancer. Oncol. Lett., 2018, 15(5), 6063-6076.
[http://dx.doi.org/10.3892/ol.2018.8123] [PMID: 29616091]
[26]
Wang, K.; Ruan, H.; Xu, T.; Liu, L.; Liu, D.; Yang, H.; Zhang, X.; Chen, K. Recent advances on the progressive mechanism and therapy in castration-resistant prostate cancer. OncoTargets Ther., 2018, 11, 3167-3178.
[http://dx.doi.org/10.2147/OTT.S159777] [PMID: 29881290]
[27]
Inoue, T.; Ogawa, O. Role of signaling transduction pathways in development of castration-resistant prostate cancer. Prostate Cancer, 2011, 2011(6)647987
[http://dx.doi.org/10.1155/2011/647987] [PMID: 22110995]
[28]
Kosaka, T.; Miyajima, A.; Shirotake, S.; Kikuchi, E.; Oya, M. Phosphorylated Akt up-regulates angiotensin II type-1 receptor expression in castration resistant prostate cancer. Prostate, 2011, 71(14), 1510-1517.
[http://dx.doi.org/10.1002/pros.21367] [PMID: 21321983]
[29]
Li, Q.; Deng, Q.; Chao, H.P.; Liu, X.; Lu, Y.; Lin, K.; Liu, B.; Tang, G.W.; Zhang, D.; Tracz, A.; Jeter, C.; Rycaj, K.; Calhoun-Davis, T.; Huang, J.; Rubin, M.A.; Beltran, H.; Shen, J.; Chatta, G.; Puzanov, I.; Mohler, J.L.; Wang, J.; Zhao, R.; Kirk, J.; Chen, X.; Tang, D.G. Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat. Commun., 2018, 9(1), 3600.
[http://dx.doi.org/10.1038/s41467-018-06067-7] [PMID: 30190514]
[30]
Holzbeierlein, J.; Lal, P.; LaTulippe, E.; Smith, A.; Satagopan, J.; Zhang, L.; Ryan, C.; Smith, S.; Scher, H.; Scardino, P.; Reuter, V.; Gerald, W.L. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am. J. Pathol., 2004, 164(1), 217-227.
[http://dx.doi.org/10.1016/S0002-9440(10)63112-4] [PMID: 14695335]
[31]
Wu, Y.; Chhipa, R.R.; Cheng, J.; Zhang, H.; Mohler, J.L.; Ip, C. Androgen receptor-mTOR crosstalk is regulated by testosterone availability: Implication for prostate cancer cell survival. Anticancer Res., 2010, 30(10), 3895-3901.
[PMID: 21036700]
[32]
Phin, S.; Moore, M.W.; Cotter, P.D. Genomic rearrangements of PTEN in prostate cancer. Front. Oncol., 2013, 3, 240.
[http://dx.doi.org/10.3389/fonc.2013.00240] [PMID: 24062990]
[33]
Chen, Y.; Chi, P.; Rockowitz, S.; Iaquinta, P.J.; Shamu, T.; Shukla, S.; Gao, D.; Sirota, I.; Carver, B.S.; Wongvipat, J.; Scher, H.I.; Zheng, D.; Sawyers, C.L. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat. Med., 2013, 19(8), 1023-1029.
[http://dx.doi.org/10.1038/nm.3216] [PMID: 23817021]
[34]
Dong, A.; Gupta, A.; Pai, R.K.; Tun, M.; Lowe, A.W. The human adenocarcinoma-associated gene, AGR2, induces expression of amphiregulin through Hippo pathway co-activator YAP1 activation. J. Biol. Chem., 2011, 286(20), 18301-18310.
[http://dx.doi.org/10.1074/jbc.M110.215707] [PMID: 21454516]
[35]
Shi, Y.; Liu, B.; Wang, C.S.; Yang, C.S. MST1 down-regulation in decreasing apoptosis of aortic dissection smooth muscle cell apoptosis. Eur. Rev. Med. Pharmacol. Sci., 2018, 22(7), 2044-2051.
[PMID: 29687861]
[36]
Loforese, G.; Malinka, T.; Keogh, A.; Baier, F.; Simillion, C.; Montani, M.; Halazonetis, T.D.; Candinas, D.; Stroka, D. Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2. EMBO Mol. Med., 2017, 9(1), 46-60.
[http://dx.doi.org/10.15252/emmm.201506089] [PMID: 27940445]
[37]
Xu, C.M.; Liu, W.W.; Liu, C.J.; Wen, C.; Lu, H.F.; Wan, F.S. Mst1 overexpression inhibited the growth of human non-small cell lung cancer in vitro and in vivo. Cancer Gene Ther., 2013, 20(8), 453-460.
[http://dx.doi.org/10.1038/cgt.2013.40] [PMID: 23928732]
[38]
Guo, C.; Tommasi, S.; Liu, L.; Yee, J.K.; Dammann, R.; Pfeifer, G.P. RASSF1A is part of a complex similar to the Drosophila Hippo/Salvador/Lats tumor-suppressor network. Curr. Biol., 2007, 17(8), 700-705.
[http://dx.doi.org/10.1016/j.cub.2007.02.055] [PMID: 17379520]
[39]
Lu, L.; Li, Y.; Kim, S.M.; Bossuyt, W.; Liu, P.; Qiu, Q.; Wang, Y.; Halder, G.; Finegold, M.J.; Lee, J.S.; Johnson, R.L. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc. Natl. Acad. Sci. USA, 2010, 107(4), 1437-1442.
[http://dx.doi.org/10.1073/pnas.0911427107] [PMID: 20080689]
[40]
Mao, R.; Liu, J.; Liu, G.; Jin, S.; Xue, Q.; Ma, L.; Fu, Y.; Zhao, N.; Xing, J.; Li, L.; Qiu, Y.; Lin, B.; Lin, B.Y. Whole genome sequencing of matched tumor, adjacent non-tumor tissues and corresponding normal blood samples of hepatocellular carcinoma patients revealed dynamic changes of the mutations profiles during hepatocarcinogenesis. Oncotarget, 2017, 8(16), 26185-26199.
[http://dx.doi.org/10.18632/oncotarget.15428] [PMID: 28412734]