Prognosis, Significance and Positive Correlation of Rab1A and p-S6K/Gli1 Expression in Gastric Cancer

Author(s): Xinyu Shao, Zhengwu Cheng, Menglin Xu, Jiading Mao, Junfeng Wang*, Chunli Zhou*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 11 , 2019

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Graphical Abstract:


Abstract:

Background: Gastric Cancer (GC) is a frequently common malignancy. Recent studies have reported Rab1A as an activator of mTORC1, and the mTOR1 pathway is involved in regulating Gli1 expression in several cancers. Only a few studies have been performed to explore the relationship between Rab1A and p-S6K/Gli1in GC.

Methods: Immunohistochemistry (IHC) was performed to explore the association of Rab1A/p-S6K/Gli1 expression and prognosis in 117 GC tissue samples and adjacent normal tissues.

Results: Our results indicated that Rab1A/p-S6K/Gli1 was significantly overexpressed in GC tissues. High expression of Rab1A was closely related to the tumor size and the depth of tumor invasion. In addition, Rab1A expression was closely related with p-S6K/Gli1 expression in GC, and high level of Rab1A/p-S6K/Gli1 caused worse prognosis of GC patients. The univariate and multivariate analysis indicated that the expression of Rab1A was an independent prognostic factor. Moreover, both high Rab1A and p-S6K expression led to a worse prognosis when compared to a single positive expression as well as both high Rab1A/Gli1 expression also led to a worse prognosis than the single positive expression of Rab1A/Gli1. Strikingly, the overexpression of p-S6K also led to a worse prognosis in Rab1A positive patients, as did Gli1.

Conclusion: Our results indicate that Rab1A/mTOR/S6K/Gli1 axis played a crucial role in GC, which may provide a novel field on targeted therapy of GC, especially for mTORC1-targeted therapy-resistant cancers.

Keywords: Gastric cancer, Gli1, prognosis, p-S6K, Rab1A, mTORC1, correlation.

[1]
Van Cutsem, E.; Sagaert, X.; Topal, B.; Haustermans, K.; Prenen, H. Gastric cancer. Lancet, 2016, 388, 2654-2664.
[2]
Gores, G.J.; Lieberman, D. Good news-bad news: Current status of GI cancers. Gastroenterology, 2016, 151, 13-16.
[3]
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136, E359-E386.
[4]
Shridhar, R.; Almhanna, K.; Hoffe, S.E.; Fulp, W.; Weber, J.; Chuong, M.D.; Meredith, K.L. Increased survival associated with surgery and radiation therapy in metastatic gastric cancer: A surveillance, epidemiology, and end results database analysis. Cancer, 2013, 119, 1636-1642.
[5]
Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer, 2013, 13, 714-726.
[6]
Bucci, C.; Alifano, P.; Cogli, L. The role of rab proteins in neuronal cells and in the trafficking of neurotrophin receptors. Membranes, 2014, 4, 642-677.
[7]
Holstein, S.A.; Hohl, R.J. Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response pathway in multiple myeloma cells. Leuk. Res., 2011, 35, 551-559.
[8]
Charng, W.L.; Yamamoto, S.; Jaiswal, M.; Bayat, V.; Xiong, B.; Zhang, K.; Sandoval, H.; David, G.; Gibbs, S.; Lu, H.C.; Chen, K.; Giagtzoglou, N.; Bellen, H.J. Drosophila Tempura, a novel protein prenyltransferase alpha subunit, regulates notch signaling via Rab1 and Rab11. PLoS Biol., 2014, 12e1001777
[9]
Tanaka, M.; Mun, S.; Harada, A.; Ohkawa, Y.; Inagaki, A.; Sano, S.; Takahashi, K.; Izumi, Y.; Osada-Oka, M.; Wanibuchi, H.; Yamagata, M.; Yukimura, T.; Miura, K.; Shiota, M.; Iwao, H. Hsc70 contributes to cancer cell survival by preventing Rab1A degradation under stress conditions. PLoS One, 2014, 9e96785
[10]
Coune, P.G.; Bensadoun, J.C.; Aebischer, P.; Schneider, B.L. Rab1A over-expression prevents Golgi apparatus fragmentation and partially corrects motor deficits in an alpha-synuclein based rat model of Parkinson’s disease. J. Parkinsons Dis., 2011, 1, 373-387.
[11]
Wu, G.; Yussman, M.G.; Barrett, T.J.; Hahn, H.S.; Osinska, H.; Hilliard, G.M.; Wang, X.; Toyokawa, T.; Yatani, A.; Lynch, R.A.; Robbins, J.; Dorn, G.W., 2nd Increased myocardial Rab GTPase expression: A consequence and cause of cardiomyopathy. Circ. Res., 2001, 89, 1130-1137.
[12]
Thomas, J.D.; Zhang, Y.J.; Wei, Y.H.; Cho, J.H.; Morris, L.E.; Wang, H.Y.; Zheng, X.F. Rab1A is an mTORC1 activator and a colorectal oncogene. Cancer Cell, 2014, 26, 754-769.
[13]
Xu, B.H.; Li, X.X.; Yang, Y.; Zhang, M.Y.; Rao, H.L.; Wang, H.Y.; Zheng, X.F. Aberrant amino acid signaling promotes growth and metastasis of hepatocellular carcinomas through Rab1A-dependent activation of mTORC1 by Rab1A. Oncotarget, 2015, 6, 20813-20828.
[14]
Wullschleger, S.; Loewith, R.; Hall, M.N. TOR signaling in growth and metabolism. Cell, 2006, 124, 471-484.
[15]
Wang, X.; Chu, Y.; Wang, W.; Yuan, W. mTORC signaling in hematopoiesis. Int. J. Hematol., 2016, 103, 510-518.
[16]
Shaw, R.J.; Cantley, L.C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature, 2006, 441, 424-430.
[17]
Han, G.; Gong, H.; Wang, Y.; Guo, S.; Liu, K. AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell. Cancer Biol. Ther., 2015, 16, 77-87.
[18]
Casey, S.C.; Amedei, A.; Aquilano, K.; Azmi, A.S.; Benencia, F.; Bhakta, D.; Bilsland, A.E.; Boosani, C.S.; Chen, S.; Ciriolo, M.R.; Crawford, S.; Fujii, H.; Georgakilas, A.G.; Guha, G.; Halicka, D.; Helferich, W.G.; Heneberg, P.; Honoki, K.; Keith, W.N.; Kerkar, S.P.; Mohammed, S.I.; Niccolai, E.; Nowsheen, S.; Vasantha Rupasinghe, H.P.; Samadi, A.; Singh, N.; Talib, W.H.; Venkateswaran, V.; Whelan, R.L.; Yang, X.; Felsher, D.W. Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin. Cancer Biol., 2015, 35, S199-S223.
[19]
Wang, Y.; Ding, Q.; Yen, C.J.; Xia, W.; Izzo, J.G.; Lang, J.Y.; Li, C.W.; Hsu, J.L.; Miller, S.A.; Wang, X.; Lee, D.F.; Hsu, J.M.; Huo, L.; Labaff, A.M.; Liu, D.; Huang, T.H.; Lai, C.C.; Tsai, F.J.; Chang, W.C.; Chen, C.H.; Wu, T.T.; Buttar, N.S.; Wang, K.K.; Wu, Y.; Wang, H.; Ajani, J.; Hung, M.C. The crosstalk of mTOR/S6K1 and Hedgehog pathways. Cancer Cell, 2012, 21, 374-387.
[20]
Li, L.; Kim, E.; Yuan, H.; Inoki, K.; Goraksha-Hicks, P.
Schiesher, R.L.; Neufeld, T.P.; Guan, K.L. Regulation of mTORC1 by the Rab and Arf GTPases. J. Biol. Chem., 2010, 285, 19705-19709.
[21]
Yang, K.; Jiang, L.; Hu, Y.; Yu, J.; Chen, H.; Yao, Y.; Zhu, X. Short hairpin RNA- mediated gene knockdown of FOXM1 inhibits the proliferation and metastasis of human colon cancer cells through reversal of epithelial-to-mesenchymal transformation. J. Exp. Clin. Cancer Res., 2015, 34, 40.
[22]
Dai, W.; Shen, G.; Qiu, J.; Zhao, X.; Gao, Q. Aberrant expression of B7-H3 in gastric adenocarcinoma promotes cancer cell metastasis. Oncol. Rep., 2014, 32, 2086-2092.
[23]
Yamashita, K.; Sakuramoto, S.; Kikuchi, S.; Katada, N.; Kobayashi, N.; Watanabe, M. Validation of staging systems for gastric cancer. Gastric Cancer, 2008, 11, 111-118.
[24]
Phyu, S.M.; Tseng, C.C.; Fleming, I.N.; Smith, T.A. Probing the PI3K/Akt/mTor pathway using (31)P-NMR spectroscopy: Routes to glycogen synthase kinase 3. Sci. Rep., 2016, 6, 36544.
[25]
Zahraoui, A.; Touchot, N.; Chardin, P.; Tavitian, A. The human Rab genes encode a family of GTP-binding proteins related to yeast YPT1 and SEC4 products involved in secretion. J. Biol. Chem., 1989, 264, 12394-12401.
[26]
Shimada, K.; Uzawa, K.; Kato, M.; Endo, Y.; Shiiba, M.; Bukawa, H.; Yokoe, H.; Seki, N.; Tanzawa, H. Aberrant expression of RAB1A in human tongue cancer. Br. J. Cancer, 2005, 92, 1915-1921.
[27]
Nikoshkov, A.; Broliden, K.; Attarha, S.; Sviatoha, V.; Hellstrom, A.C.; Mints, M.; Andersson, S. Expression pattern of the PRDX2, RAB1A, RAB1B, RAB5A and RAB25 genes in normal and cancer cervical tissues. Int. J. Oncol., 2015, 46, 107-112.
[28]
Xu, H.; Qian, M.; Zhao, B.; Wu, C.; Maskey, N.; Song, H.; Li, D.; Song, J.; Hua, K.; Fang, L. Inhibition of RAB1A suppresses epithelial-mesenchymal transition and proliferation of triple-negative breast cancer cells. Oncol. Rep., 2017, 37, 1619-1626.
[29]
Sun, T.; Wang, X.; He, H.H.; Sweeney, C.J.; Liu, S.X.; Brown, M.; Balk, S.; Lee, G.S.; Kantoff, P.W. MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A. Oncogene, 2014, 33, 2790-2800.
[30]
Wang, X.; Liu, F.; Qin, X.; Huang, T.; Huang, B.; Zhang, Y.; Jiang, B. Expression of Rab1A is upregulated in human lung cancer and associated with tumor size and T stage. Aging, 2016, 8, 2790-2798.
[31]
Wang, X.; Yao, Y.; Zhu, X. The influence of aberrant expression of GLI1/p-S6K on colorectal cancer. Biochem. Biophys. Res. Commun., 2018, 503, 3198-3204.
[32]
Wang, Z.K.; Cheng, Z.W.; Chen, S.J.; Zhu, X.G.; Gu, Y.P.; Yang, X.D.; Sun, L.; Liu, W.T.; Zhang, Y.J.; Yuan, J.F.; Tian, K.J.; Yao, Y.Z.; He, S.B. Aberrant expression of Rab1A and its prognostic significance in human colorectal cancer. Eur. Rev. Med. Pharmacol. Sci., 2018, 22, 4509-4517.
[33]
Xu, B.; Huang, C.; Yang, X.; Li, X.; Li, L.; Ding, Y. Significance and prognostic role of human epidermal growth factor receptor 2 and RAB1A expression in gastric cancer. Oncol. Lett., 2018, 15, 5185-5192.
[34]
Wang, B.; Yu, T.; Hu, Y.; Xiang, M.; Peng, H.; Lin, Y.; Han, L.; Zhang, L. Prognostic role of Gli1 expression in breast cancer: A meta-analysis. Oncotarget, 2017, 8, 81088-81097.
[35]
Hou, P.; Kang, Y.; Luo, J. Hypoxia-mediated miR-212-3p downregulation enhances progression of intrahepatic cholangiocarcinoma through upregulation of Rab1a. Cancer Biol. Ther., 2018, 19(11), 984-993.


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Article Details

VOLUME: 19
ISSUE: 11
Year: 2019
Page: [1359 - 1367]
Pages: 9
DOI: 10.2174/1871520619666190416110851
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