WWC3 Downregulation Correlates with Poor Prognosis and Inhibition of Hippo Signaling in Human Gastric Cancer

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2017 Jun 28

PMID 28652775

Citations 12

Authors

Jiabin Hou

Jin Zhou

Affiliations

Soon will be listed here.

Abstract

The aim of this study was to investigate the clinicopathological significance and biological roles of WWC3 in human gastric cancer (GC). Clinical significance of WWC3 in human GCs was examined by using immunohistochemistry (IHC). WWC3 was downregulated in 48 of 111 human GCs, and its downregulation was associated with advanced stage, positive nodal status, and higher relapse rate. Importantly, WWC3 downregulation correlated with poor survival. It was also found that WWC3 protein expression was downregulated in GC cell lines compared with normal cell line GES-1. On one hand, WWC3 overexpression inhibited the cell growth rate and invading ability in HGC-27 cell line. On the other hand, depleting WWC3 by small interfering RNA (siRNA) promoted proliferation rate and invading ability in the SGC-7901 cell line. In addition, cell cycle analysis showed that WWC3 overexpression inhibited while its depletion accelerated cell cycle progression at the G1/S transition. Western blot (WB) analysis demonstrated that WWC3 repressed cyclin D1 and cyclin E while upregulated p27 expression. Luciferase reporter assay showed that WWC3 activated Hippo signaling pathway by suppressing TEAD transcription activity, with downregulation of total and nuclear YAP and its target CTGF. WWC3 siRNA depletion exhibited the opposite effects. In conclusion, this study indicates that WWC3 serves as a tumor suppressor in GC by activating Hippo signaling.

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References

Stauffer S, Chen X, Zhang L, Chen Y, Dong J . KIBRA promotes prostate cancer cell proliferation and motility. FEBS J. 2016; 283(10):1800-11. PMC: 4880424. DOI: 10.1111/febs.13718. View

Zhang J, Wang G, Chu S, Zhu J, Zhang R, Lu W . Loss of large tumor suppressor 1 promotes growth and metastasis of gastric cancer cells through upregulation of the YAP signaling. Oncotarget. 2016; 7(13):16180-93. PMC: 4941306. DOI: 10.18632/oncotarget.7568. View

Moleirinho S, Chang N, Sims A, Tilston-Lunel A, Angus L, Steele A . KIBRA exhibits MST-independent functional regulation of the Hippo signaling pathway in mammals. Oncogene. 2012; 32(14):1821-30. DOI: 10.1038/onc.2012.196. View

Duning K, Schurek E, Schluter M, Bayer M, Reinhardt H, Schwab A . KIBRA modulates directional migration of podocytes. J Am Soc Nephrol. 2008; 19(10):1891-903. PMC: 2551571. DOI: 10.1681/ASN.2007080916. View

Wennmann D, Schmitz J, Wehr M, Krahn M, Koschmal N, Gromnitza S . Evolutionary and molecular facts link the WWC protein family to Hippo signaling. Mol Biol Evol. 2014; 31(7):1710-23. DOI: 10.1093/molbev/msu115. View

Yu J, Zheng Y, Dong J, Klusza S, Deng W, Pan D . Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell. 2010; 18(2):288-99. PMC: 2858562. DOI: 10.1016/j.devcel.2009.12.012. View

Tsai H, Su H, Huang C, Fong Y, Hsu C, Tang C . CTGF increases matrix metalloproteinases expression and subsequently promotes tumor metastasis in human osteosarcoma through down-regulating miR-519d. Oncotarget. 2014; 5(11):3800-12. PMC: 4116521. DOI: 10.18632/oncotarget.1998. View

Jeong S, Ko G, Cho Y, Lee Y, Cho B, Ha W . Pyrophosphatase overexpression is associated with cell migration, invasion, and poor prognosis in gastric cancer. Tumour Biol. 2012; 33(6):1889-98. DOI: 10.1007/s13277-012-0449-5. View

Pradeep A, Sharma C, Sathyanarayana P, Albanese C, Fleming J, Wang T . Gastrin-mediated activation of cyclin D1 transcription involves beta-catenin and CREB pathways in gastric cancer cells. Oncogene. 2004; 23(20):3689-99. DOI: 10.1038/sj.onc.1207454. View

10.

Hill V, Dunwell T, Catchpoole D, Krex D, Brini A, Griffiths M . Frequent epigenetic inactivation of KIBRA, an upstream member of the Salvador/Warts/Hippo (SWH) tumor suppressor network, is associated with specific genetic event in B-cell acute lymphocytic leukemia. Epigenetics. 2010; 6(3):326-32. PMC: 3092681. DOI: 10.4161/epi.6.3.14404. View

11.

Rosse C, Formstecher E, Boeckeler K, Zhao Y, Kremerskothen J, White M . An aPKC-exocyst complex controls paxillin phosphorylation and migration through localised JNK1 activation. PLoS Biol. 2009; 7(11):e1000235. PMC: 2762617. DOI: 10.1371/journal.pbio.1000235. View

12.

Zhou Z, Zhu J, Xu Z . RNA interference mediated YAP gene silencing inhibits invasion and metastasis of human gastric cancer cell line SGC-7901. Hepatogastroenterology. 2011; 58(112):2156-61. DOI: 10.5754/hge11234. View

13.

Hsueh Y, Chen H, Wu S, Wang T, Chen J, Ma D . Lysophosphatidic acid induces YAP-promoted proliferation of human corneal endothelial cells via PI3K and ROCK pathways. Mol Ther Methods Clin Dev. 2015; 2:15014. PMC: 4445000. DOI: 10.1038/mtm.2015.14. View

14.

Mayer B, Funke I, Johnson J . High expression of a Lewis(x)-related epitope in gastric carcinomas indicates metastatic potential and poor prognosis. Gastroenterology. 1996; 111(6):1433-46. DOI: 10.1016/s0016-5085(96)70004-5. View

15.

Li N, Yu N, Wang J, Xi H, Lu W, Xu H . miR-222/VGLL4/YAP-TEAD1 regulatory loop promotes proliferation and invasion of gastric cancer cells. Am J Cancer Res. 2015; 5(3):1158-68. PMC: 4449443. View

16.

Jia Y, Dong B, Tang L, Liu Y, Du H, Yuan P . Apoptosis index correlates with chemotherapy efficacy and predicts the survival of patients with gastric cancer. Tumour Biol. 2012; 33(4):1151-8. DOI: 10.1007/s13277-012-0357-8. View

17.

Braig S, Wallner S, Junglas B, Fuchshofer R, Bosserhoff A . CTGF is overexpressed in malignant melanoma and promotes cell invasion and migration. Br J Cancer. 2011; 105(2):231-8. PMC: 3142806. DOI: 10.1038/bjc.2011.226. View

18.

Wang R, Ding X, Zhou S, Li M, Sun L, Xu X . Microrna-26b attenuates monocrotaline-induced pulmonary vascular remodeling via targeting connective tissue growth factor (CTGF) and cyclin D1 (CCND1). Oncotarget. 2016; 7(45):72746-72757. PMC: 5341941. DOI: 10.18632/oncotarget.10125. View

19.

Kothapalli D, Grotendorst G . CTGF modulates cell cycle progression in cAMP-arrested NRK fibroblasts. J Cell Physiol. 1999; 182(1):119-26. DOI: 10.1002/(SICI)1097-4652(200001)182:1<119::AID-JCP13>3.0.CO;2-4. View

20.

Bray F, Ren J, Masuyer E, Ferlay J . Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer. 2012; 132(5):1133-45. DOI: 10.1002/ijc.27711. View