Browse > Article
http://dx.doi.org/10.14348/molcells.2020.0093

WWC1 and NF2 Prevent the Development of Intrahepatic Cholangiocarcinoma by Regulating YAP/TAZ Activity through LATS in Mice  

Park, Jaeoh (Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology (KAIST))
Kim, Jeong Sik (Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology (KAIST))
Nahm, Ji Hae (Department of Pathology, Yonsei University College of Medicine, Gangnam Severance Hospital)
Kim, Sang-Kyum (Department of Pathology, Yonsei University College of Medicine, Severance Hospital Seoul)
Lee, Da-Hye (Center for Bioanalysis, Korea Research Institute for Standards and Science)
Lim, Dae-Sik (Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology (KAIST))
Publication Information
Molecules and Cells / v.43, no.5, 2020 , pp. 491-499 More about this Journal
Abstract
Hippo signaling acts as a tumor suppressor pathway by inhibiting the proliferation of adult stem cells and progenitor cells in various organs. Liver-specific deletion of Hippo pathway components in mice induces liver cancer development through activation of the transcriptional coactivators, YAP and TAZ, which exhibit nuclear enrichment and are activated in numerous types of cancer. The upstream-most regulators of Warts, the Drosophila ortholog of mammalian LATS1/2, are Kibra, Expanded, and Merlin. However, the roles of the corresponding mammalian orthologs, WWC1, FRMD6 and NF2, in the regulation of LATS1/2 activity and liver tumorigenesis in vivo are not fully understood. Here, we show that deletion of both Wwc1 and Nf2 in the liver accelerates intrahepatic cholangiocarcinoma (iCCA) development through activation of YAP/TAZ. Additionally, biliary epithelial cell-specific deletion of both Lats1 and Lats2 using a Sox9-CreERT2 system resulted in iCCA development through hyperactivation of YAP/TAZ. These findings suggest that WWC1 and NF2 cooperate to promote suppression of cholangiocarcinoma development by inhibiting the oncogenic activity of YAP/TAZ via LATS1/2.
Keywords
cholangiocarcinoma; Hippo pathway; NF2; WWC1; YAP;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Zhou, D., Conrad, C., Xia, F., Park, J.S., Payer, B., Yin, Y., Lauwers, G.Y., Thasler, W., Lee, J.T., Avruch, J., et al. (2009). Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16, 425-438.   DOI
2 Moon, K.H., Kim, H.T., Lee, D., Rao, M.B., Levine, E.M., Lim, D.S., and Kim, J.W. (2018). Differential expression of NF2 in neuroepithelial compartments is necessary for mammalian eye development. Dev. Cell 44, 13-28.e3.   DOI
3 Nishio, M., Sugimachi, K., Goto, H., Wang, J., Morikawa, T., Miyachi, Y., Takano, Y., Hikasa, H., Itoh, T., Suzuki, S.O., et al. (2016). Dysregulated YAP1/TAZ and TGF-beta signaling mediate hepatocarcinogenesis in Mob1a/1bdeficient mice. Proc. Natl. Acad. Sci. U. S. A. 113, E71-E80.   DOI
4 Pan, D. (2007). Hippo signaling in organ size control. Genes Dev. 21, 886-897.   DOI
5 Park, G.S., Oh, H., Kim, M., Kim, T., Johnson, R.L., Irvine, K.D., and Lim, D.S. (2016). An evolutionarily conserved negative feedback mechanism in the Hippo pathway reflects functional difference between LATS1 and LATS2. Oncotarget 7, 24063-24075.   DOI
6 Pei, T., Li, Y., Wang, J., Wang, H., Liang, Y., Shi, H., Sun, B., Yin, D., Sun, J., Song, R., et al. (2015). YAP is a critical oncogene in human cholangiocarcinoma. Oncotarget 6, 17206-17220.   DOI
7 Rhee, H., Ko, J.E., Chung, T., Jee, B.A., Kwon, S.M., Nahm, J.H., Seok, J.Y., Yoo, J.E., Choi, J.S., Thorgeirsson, S.S., et al. (2018). Transcriptomic and histopathological analysis of cholangiolocellular differentiation trait in intrahepatic cholangiocarcinoma. Liver Int. 38, 113-124.   DOI
8 Rizvi, S., Fischbach, S.R., Bronk, S.F., Hirsova, P., Krishnan, A., Dhanasekaran, R., Smadbeck, J.B., Smoot, R.L., Vasmatzis, G., and Gores, G.J. (2018). YAPassociated chromosomal instability and cholangiocarcinoma in mice. Oncotarget 9, 5892-5905.   DOI
9 Song, H., Mak, K.K., Topol, L., Yun, K., Hu, J., Garrett, L., Chen, Y., Park, O., Chang, J., Simpson, R.M., et al. (2010). Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc. Natl. Acad. Sci. U. S. A. 107, 1431-1436.   DOI
10 Baumgartner, R., Poernbacher, I., Buser, N., Hafen, E., and Stocker, H. (2010). The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev. Cell 18, 309-316.   DOI
11 Benhamouche, C.M., Saotome, I., Gladden, A.B., Liu, C.H., Giovannini, M., and McClatchey, A.I. (2010). Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev. 24, 1718-1730.   DOI
12 Camargo, F.D., Gokhale, S., Johnnidis, J.B., Fu, D., Bell, G.W., Jaenisch, R., and Brummelkamp, T.R. (2007). YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Biol. 17, 2054-2060.   DOI
13 Choi, W., Kim, J., Park, J., Lee, D.H., Hwang, D., Kim, J.H., Ashktorab, H., Smoot, D., Kim, S.Y., Choi, C., et al. (2018). YAP/TAZ initiates gastric tumorigenesis via upregulation of MYC. Cancer Res. 78, 3306-3320.   DOI
14 Cordenonsi, M., Zanconato, F., Azzolin, L., Forcato, M., Rosato, A., Frasson, C., Inui, M., Montagner, M., Parenti, A.R., Poletti, A., et al. (2011). The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147, 759-772.   DOI
15 Genevet, A., Wehr, M.C., Brain, R., Thompson, B.J., and Tapon, N. (2010). Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev. Cell 18, 300-308.   DOI
16 Yu, F.X., Zhao, B., and Guan, K.L. (2015). Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163, 811-828.   DOI
17 Su, T., Ludwig, M.Z., Xu, J., and Fehon, R.G. (2017). Kibra and Merlin activate the Hippo pathway spatially distinct from and independent of Expanded. Dev. Cell 40, 478-490.e3.   DOI
18 Van Haele, M., Moya, I.M., Karaman, R., Rens, G., Snoeck, J., Govaere, O., Nevens, F., Verslype, C., Topal, B., Monbaliu, D., et al. (2019). YAP and TAZ heterogeneity in primary liver cancer: an analysis of its prognostic and diagnostic role. Int. J. Mol. Sci. 20, 638.   DOI
19 Wang, T., Qin, Z.Y., Wen, L.Z., Guo, Y., Liu, Q., Lei, Z.J., Pan, W., Liu, K.J., Wang, X.W., Lai, S.J., et al. (2018). Epigenetic restriction of Hippo signaling by MORC2 underlies stemness of hepatocellular carcinoma cells. Cell Death Differ. 25, 2086-2100.   DOI
20 Zhang, N., Bai, H., David, K.K., Dong, J., Zheng, Y., Cai, J., Giovannini, M., Liu, P., Anders, R.A., and Pan, D. (2010). The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19, 27-38.   DOI
21 Hayashi, A., Misumi, K., Shibahara, J., Arita, J., Sakamoto, Y., Hasegawa, K., Kokudo, N., and Fukayama, M. (2016). Distinct clinicopathologic and genetic features of 2 histologic subtypes of intrahepatic cholangiocarcinoma. Am. J. Surg. Pathol. 40, 1021-1030.   DOI
22 Giovannini, M., Robanus-Maandag, E., van der Valk, M., Niwa-Kawakita, M., Abramowski, V., Goutebroze, L., Woodruff, J.M., Berns, A., and Thomas, G. (2000). Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 14, 1617-1630.
23 Gregorieff, A., Liu, Y., Inanlou, M.R., Khomchuk, Y., and Wrana, J.L. (2015). Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer. Nature 526, 715-718.   DOI
24 Halder, G. and Johnson, R.L. (2011). Hippo signaling: growth control and beyond. Development 138, 9-22.   DOI
25 Hayashi, S., Yokoyama, H., and Tamura, K. (2015). Roles of Hippo signaling pathway in size control of organ regeneration. Dev. Growth Differ. 57, 341-351.   DOI
26 Heallen, T., Morikawa, Y., Leach, J., Tao, G., Willerson, J.T., Johnson, R.L., and Martin, J.F. (2013). Hippo signaling impedes adult heart regeneration. Development 140, 4683-4690.   DOI
27 Heallen, T., Zhang, M., Wang, J., Bonilla-Claudio, M., Klysik, E., Johnson, R.L., and Martin, J.F. (2011). Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458-461.   DOI
28 Hermann, A., Wennmann, D.O., Gromnitza, S., Edeling, M., Van Marck, V., Sudol, M., Schaefer, L., Duning, K., Weide, T., Pavenstadt, H., et al. (2018). WW and C2 domain-containing proteins regulate hepatic cell differentiation and tumorigenesis through the hippo signaling pathway. Hepatology 67, 1546-1559.   DOI
29 Kopp, J.L., Dubois, C.L., Schaffer, A.E., Hao, E., Shih, H.P., Seymour, P.A., Ma, J., and Sander, M. (2011). Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 138, 653-665.   DOI
30 Kim, M., Kim, M., Lee, S., Kuninaka, S., Saya, H., Lee, H., Lee, S., and Lim, D.S. (2013). cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes. EMBO J. 32, 1543-1555.   DOI
31 Lee, D.H., Park, J.O., Kim, T.S., Kim, S.K., Kim, T.H., Kim, M.C., Park, G.S., Kim, J.H., Kuninaka, S., Olson, E.N., et al. (2016). LATS-YAP/TAZ controls lineage specification by regulating TGFbeta signaling and Hnf4alpha expression during liver development. Nat. Commun. 7, 11961.   DOI
32 Lee, K.P., Lee, J.H., Kim, T.S., Kim, T.H., Park, H.D., Byun, J.S., Kim, M.C., Jeong, W.I., Calvisi, D.F., Kim, J.M., et al. (2010). The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc. Natl. Acad. Sci. U. S. A. 107, 8248-8253.   DOI
33 Lu, L., Finegold, M.J., and Johnson, R.L. (2018). Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration. Exp. Mol. Med. 50, e423.   DOI
34 Makuch, L., Volk, L., Anggono, V., Johnson, R.C., Yu, Y., Duning, K., Kremerskothen, J., Xia, J., Takamiya, K., and Huganir, R.L. (2011). Regulation of AMPA receptor function by the human memory-associated gene KIBRA. Neuron 71, 1022-1029.   DOI
35 Marti, P., Stein, C., Blumer, T., Abraham, Y., Dill, M.T., Pikiolek, M., Orsini, V., Jurisic, G., Megel, P., Makowska, Z., et al. (2015). YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors. Hepatology 62, 1497-1510.   DOI