PRL-3 promotes the peritoneal metastasis of gastric cancer through the PI3K/Akt signaling pathway by regulating PTEN

Xiong,Jianbo; Li,Zhengrong; Zhang,Yang; Li,Daojiang; Zhang,Guoyang; Luo,Xianshi; Jie,Zhigang; Liu,Yi; Cao,Yi; Le,Zhibiao; Tan,Shengxing; Zou,Wenyu; Gong,Peitao; Qiu,Lingyu; Li,Yuanyuan; Wang,Huan; Chen,Heping

doi:10.3892/or.2016.5030

PRL-3 promotes the peritoneal metastasis of gastric cancer through the PI3K/Akt signaling pathway by regulating PTEN

Authors:
- Jianbo Xiong
- Zhengrong Li
- Yang Zhang
- Daojiang Li
- Guoyang Zhang
- Xianshi Luo
- Zhigang Jie
- Yi Liu
- Yi Cao
- Zhibiao Le
- Shengxing Tan
- Wenyu Zou
- Peitao Gong
- Lingyu Qiu
- Yuanyuan Li
- Huan Wang
- Heping Chen
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Affiliations: Department of Gastrointestinal Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330000, P.R. China, The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: August 23, 2016 https://doi.org/10.3892/or.2016.5030
Pages: 1819-1828
Copyright: © Xiong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Peritoneal metastasis is the most frequent cause of death in patients with advanced gastric carcinoma (GC). The phosphatase of regenerating liver-3 (PRL-3) is recognized as an oncogene and plays an important role in GC peritoneal metastasis. However, the mechanism of how PRL-3 regulates GC invasion and metastasis is unknown. In the present study, we found that PRL-3 presented with high expression in GC with peritoneal metastasis, but phosphatase and tensin homologue (PTEN) was weakly expressed. The p-PTEN/PTEN ratio was also higher in GC with peritoneal metastasis than that in the normal gastric tissues. We also found the same phenomenon when comparing the gastric mucosa cell line with the GC cell lines. After constructing a wild-type and a mutant-type plasmid without enzyme activity and transfecting them into GC SGC7901 cells, we showed that only PRL-3 had enzyme activity to downregulate PTEN and cause PTEN phosphorylation. The results also showed that PRL-3 increased the expression levels of MMP-2/MMP-9 and promoted the migration and invasion of the SGC7901 cells. Knockdown of PRL-3 decreased the expression levels of MMP-2/MMP-9 significantly, which further inhibited the migration and invasion of the GC cells. PRL-3 also increased the expression ratio of p-Akt/Akt, which indicated that PRL-3 may mediate the PI3K/Akt pathway to promote GC metastasis. When we transfected the PTEN siRNA plasmid into the PRL-3 stable low expression GC cells, the expression of p-Akt, MMP-2 and MMP-9 was reversed. In conclusion, our results provide a bridge between PRL-3 and PTEN; PRL-3 decreased the expression of PTEN as well as increased the level of PTEN phosphorylation and inactivated it, consequently activating the PI3K/Akt signaling pathway, and upregulating MMP-2/MMP-9 expression to promote GC cell peritoneal metastasis.

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1	Globocan: 2012, Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed March 31, 2014.
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
3	De Vita F, Vecchione L, Galizia G, Di Martino N, Fabozzi T, Catalano G, Ciardiello F and Orditura M: Perspectives in adjuvant therapy of gastric cancer. Oncology. 77(Suppl 1): S38–S42. 2009. View Article : Google Scholar
4	Kagawa S, Shigeyasu K, Ishida M, Watanabe M, Tazawa H, Nagasaka T, Shirakawa Y and Fujiwara T: Molecular diagnosis and therapy for occult peritoneal metastasis in gastric cancer patients. World J Gastroenterol. 20:17796–17803. 2014.PubMed/NCBI
5	Bando E, Yonemura Y, Takeshita Y, Taniguchi K, Yasui T, Yoshimitsu Y, Fushida S, Fujimura T, Nishimura G and Miwa K: Intraoperative lavage for cytological examination in 1,297 patients with GC. Am J Surg. 178:256–262. 1999. View Article : Google Scholar : PubMed/NCBI
6	Turaga KK, Gamblin TC and Pappas S: Surgical treatment of peritoneal carcinomatosis from gastric cancer. Int J Surg Oncol. 2012:4056522012.PubMed/NCBI
7	Bessette DC, Qiu D and Pallen CJ: PRL PTPs: Mediators and markers of cancer progression. Cancer Metastasis Rev. 27:231–252. 2008. View Article : Google Scholar : PubMed/NCBI
8	Dong Q, Ding X, Chang B, Wang H and Wang A: PRL-3 promotes migration and invasion and is associated with poor prognosis in salivary adenoid cystic carcinoma. J Oral Pathol Med. 45:111–118. 2016. View Article : Google Scholar
9	Kato H, Semba S, Miskad UA, Seo Y, Kasuga M and Yokozaki H: High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer: A predictive molecular marker of metachronous liver and lung metastases. Clin Cancer Res. 10:7318–7328. 2004. View Article : Google Scholar : PubMed/NCBI
10	Guo K, Li J, Tang JP, Koh V, Gan BQ and Zeng Q: Catalytic domain of PRL-3 plays an essential role in tumor metastasis: Formation of PRL-3 tumors inside the blood vessels. Cancer Biol Ther. 3:945–951. 2004. View Article : Google Scholar : PubMed/NCBI
11	Wu X, Zeng H, Zhang X, Zhao Y, Sha H, Ge X, Zhang M, Gao X and Xu Q: Phosphatase of regenerating liver-3 promotes motility and metastasis of mouse melanoma cells. Am J Pathol. 164:2039–2054. 2004. View Article : Google Scholar : PubMed/NCBI
12	Dai N, Lu AP, Shou CC and Li JY: Expression of phosphatase regenerating liver 3 is an independent prognostic indicator for gastric cancer. World J Gastroenterol. 15:1499–1505. 2009. View Article : Google Scholar : PubMed/NCBI
13	Zeng Q, Dong JM, Guo K, Li J, Tan HX, Koh V, Pallen CJ, Manser E and Hong W: PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. Cancer Res. 63:2716–2722. 2003.PubMed/NCBI
14	Li ZR, Wang Z, Zhu BH, He YL, Peng JS, Cai SR, Ma JP and Zhan WH: Association of tyrosine PRL-3 phosphatase protein expression with peritoneal metastasis of GC and prognosis. Surg Today. 37:646–651. 2007. View Article : Google Scholar
15	Xing X, Lian S, Hu Y, Li Z, Zhang L, Wen X, Du H, Jia Y, Zheng Z, Meng L, et al: Phosphatase of regenerating liver-3 (PRL-3) is associated with metastasis and poor prognosis in GC. J Transl Med. 11:309. 2013. View Article : Google Scholar
16	Miskad UA, Semba S, Kato H and Yokozaki H: Expression of PRL-3 phosphatase in human gastric carcinomas: Close correlation with invasion and metastasis. Pathobiology. 71:176–184. 2004. View Article : Google Scholar : PubMed/NCBI
17	Wang Z, Cai SR, He YL, Zhan WH, Chen CQ, Cui J, Wu WH, Wu H, Song W, Zhang CH, et al: High expression of PRL-3 can promote growth of gastric cancer and exhibits a poor prognostic impact on patients. Ann Surg Oncol. 16:208–219. 2009. View Article : Google Scholar
18	Li Z, Cao Y, Jie Z, Liu Y, Li Y, Li J, Zhu G, Liu Z, Tu Y, Peng G, et al: miR-495 and miR-551a inhibit the migration and invasion of human gastric cancer cells by directly interacting with PRL-3. Cancer Lett. 323:41–47. 2012. View Article : Google Scholar : PubMed/NCBI
19	Waite KA and Eng C: Protean PTEN: Form and function. Am J Hum Genet. 70:829–844. 2002. View Article : Google Scholar : PubMed/NCBI
20	Bermúdez Brito M, Goulielmaki E and Papakonstanti EA: Focus on PTEN regulation. Front Oncol. 5:1662015. View Article : Google Scholar : PubMed/NCBI
21	Ye B, Jiang LL, Xu HT, Zhou DW and Li ZS: Expression of PI3K/AKT pathway in gastric cancer and its blockade suppresses tumor growth and metastasis. Int J Immunopathol Pharmacol. 25:627–636. 2012.PubMed/NCBI
22	Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP and Tonks NK: The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci USA. 95:13513–13518. 1998. View Article : Google Scholar : PubMed/NCBI
23	Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP and Mak TW: Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 95:29–39. 1998. View Article : Google Scholar : PubMed/NCBI
24	Cully M, You H, Levine AJ and Mak TW: Beyond PTEN mutations: The PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 6:184–192. 2006. View Article : Google Scholar : PubMed/NCBI
25	Wadhwa R, Song S, Lee JS, Yao Y, Wei Q and Ajani JA: Gastric cancer-molecular and clinical dimensions. Nat Rev Clin Oncol. 10:643–655. 2013. View Article : Google Scholar : PubMed/NCBI
26	Li NA, Wang W, Xu B and Gong H: miR-196b regulates gastric cancer cell proliferation and invasion via PI3K/AKT/mTOR signaling pathway. Oncol Lett. 11:1745–1749. 2016.PubMed/NCBI
27	Akrami H, Mahmoodi F, Havasi S and Sharifi A: PlGF knockdown inhibited tumor survival and migration in gastric cancer cell via PI3K/Akt and p38MAPK pathways. Cell Biochem Funct. 34:173–180. 2016. View Article : Google Scholar : PubMed/NCBI
28	Sun L, Liu L, Liu X, Wang Y, Li M, Yao L, Yang J, Ji G, Guo C, Pan Y, et al: MGr1-Ag/37LRP induces cell adhesion-mediated drug resistance through FAK/PI3K and MAPK pathway in gastric cancer. Cancer Sci. 105:651–659. 2014. View Article : Google Scholar : PubMed/NCBI
29	Wang H, Quah SY, Dong JM, Manser E, Tang JP and Zeng Q: PRL-3 down-regulates PTEN expression and signals through PI3K to promote epithelial-mesenchymal transition. Cancer Res. 67:2922–2926. 2007. View Article : Google Scholar : PubMed/NCBI
30	Wang H, Vardy LA, Tan CP, Loo JM, Guo K, Li J, Lim SG, Zhou J, Chng WJ, Ng SB, et al: PCBP1 suppresses the translation of metastasis-associated PRL-3 phosphatase. Cancer Cell. 18:52–62. 2010. View Article : Google Scholar : PubMed/NCBI
31	Fang XY, Song R, Chen W, Yang YY, Gu YH, Shu YQ, Wu XD, Wu XF, Sun Y, Shen Y, et al: PRL-3 promotes the malignant progression of melanoma via triggering dephosphorylation and cytoplasmic localization of NHERF1. J Invest Dermatol. 135:2273–2282. 2015. View Article : Google Scholar : PubMed/NCBI
32	Chaffer CL and Weinberg RA: A perspective on cancer cell metastasis. Science. 331:1559–1564. 2011. View Article : Google Scholar : PubMed/NCBI
33	Brinckerhoff CE and Matrisian LM: Matrix metalloproteinases: A tail of a frog that became a prince. Nat Rev Mol Cell Biol. 3:207–214. 2002. View Article : Google Scholar : PubMed/NCBI
34	Peng L, Xing X, Li W, Qu L, Meng L, Lian S, Jiang B, Wu J and Shou C: PRL-3 promotes the motility, invasion, and metastasis of LoVo colon cancer cells through PRL-3-integrin beta1-ERK1/2 and-MMP2 signaling. Mol Cancer. 8:1102009. View Article : Google Scholar : PubMed/NCBI
35	Ye Z, Al-Aidaroos AQ, Park JE, Yuen HF, Zhang SD, Gupta A, Lin Y, Shen HM and Zeng Q: PRL-3 activates mTORC1 in cancer progression. Sci Rep. 5:170462015. View Article : Google Scholar : PubMed/NCBI
36	Li WJ, Xing XF, Qu LK, Meng L and Shou CC: Construction and expression of PRL-3 plasmid with C104S point mutation and CAAX deletion. Beijing Da Xue Xue Bao. 41:516–520. 2009.In Chinese. PubMed/NCBI
37	Pascaru M, Tanase C, Vacaru AM, Boeti P, Neagu E, Popescu I and Szedlacsek SE: Analysis of molecular determinants of PRL-3. J Cell Mol Med. 13:3141–3150. 2009. View Article : Google Scholar
38	Kozlov G, Cheng J, Ziomek E, Banville D, Gehring K and Ekiel I: Structural insights into molecular function of the metastasis-associated phosphatase PRL-3. J Biol Chem. 279:11882–11889. 2004. View Article : Google Scholar : PubMed/NCBI
39	McParland V, Varsano G, Li X, Thornton J, Baby J, Aravind A, Meyer C, Pavic K, Rios P and Köhn M: The metastasis-promoting phosphatase PRL-3 shows activity toward phosphoinositides. Biochemistry. 50:7579–7590. 2011. View Article : Google Scholar : PubMed/NCBI
40	Matter WF, Estridge T, Zhang C, Belagaje R, Stancato L, Dixon J, Johnson B, Bloem L, Pickard T, Donaghue M, et al: Role of PRL-3, a human muscle-specific tyrosine phosphatase, in angiotensin-II signaling. Biochem Biophys Res Commun. 283:1061–1068. 2001. View Article : Google Scholar : PubMed/NCBI
41	Fiordalisi JJ, Keller PJ and Cox AD: PRL tyrosine phosphatases regulate rho family GTPases to promote invasion and motility. Cancer Res. 66:3153–3161. 2006. View Article : Google Scholar : PubMed/NCBI
42	Jian M, Nan L, Guocheng J, Qingfu Z, Xueshan Q and Enhua W: Downregulating PRL-3 inhibit migration and invasion of lung cancer cell via RhoA and mDia1. Tumori. 98:370–376. 2012.PubMed/NCBI
43	Li Z, Zhan W, Wang Z, Zhu B, He Y, Peng J, Cai S and Ma J: Inhibition of PRL-3 gene expression in gastric cancer cell line SGC7901 via microRNA suppressed reduces peritoneal metastasis. Biochem Biophys Res Commun. 348:229–237. 2006. View Article : Google Scholar : PubMed/NCBI
44	Liu Y, Zheng P, Liu Y, Ji T, Liu X, Yao S, Cheng X, Li Y, Chen L, Xiao Z, et al: An epigenetic role for PRL-3 as a regulator of H3K9 methylation in colorectal cancer. Gut. 62:571–581. 2013. View Article : Google Scholar
45	Molleví DG, Aytes A, Padullés L, Martínez-Iniesta M, Baixeras N, Salazar R, Ramos E, Figueras J, Capella G and Villanueva A: PRL-3 is essentially overexpressed in primary colorectal tumours and associates with tumour aggressiveness. Br J Cancer. 99:1718–1725. 2008. View Article : Google Scholar : PubMed/NCBI
46	Mayinuer A, Yasen M, Mogushi K, Obulhasim G, Xieraili M, Aihara A, Tanaka S, Mizushima H, Tanaka H and Arii S: Upregulation of protein tyrosine phosphatase type IVA member 3 (PTP4A3/PRL-3) is associated with tumor differentiation and a poor prognosis in human hepatocellular carcinoma. Ann Surg Oncol. 20:305–317. 2013. View Article : Google Scholar :
47	Khapare N, Kundu ST, Sehgal L, Sawant M, Priya R, Gosavi P, Gupta N, Alam H, Karkhanis M, Naik N, et al: Plakophilin3 loss leads to an increase in PRL3 levels promoting K8 dephosphorylation, which is required for transformation and metastasis. PLoS One. 7:e385612012. View Article : Google Scholar : PubMed/NCBI
48	Zhang S, Zhang Y, Zhuang Y, Wang J, Ye J, Zhang S, Wu J, Yu K and Han Y: Matrine induces apoptosis in human acute myeloid leukemia cells via the mitochondrial pathway and Akt inactivation. PLoS One. 7:e468532012. View Article : Google Scholar : PubMed/NCBI
49	Bessette DC, Wong PC and Pallen CJ: PRL-3: A metastasis-associated phosphatase in search of a function. Cells Tissues Organs. 185:232–236. 2007. View Article : Google Scholar : PubMed/NCBI
50	Xu H, Lai W, Zhang Y, Liu L, Luo X, Zeng Y, Wu H, Lan Q and Chu Z: Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner. BMC Cancer. 14:3302014. View Article : Google Scholar : PubMed/NCBI
51	Miskad UA, Semba S, Kato H, Matsukawa Y, Kodama Y, Mizuuchi E, Maeda N, Yanagihara K and Yokozaki H: High PRL-3 expression in human gastric cancer is a marker of metastasis and grades of malignancies: An in situ hybridization study. Virchows Archiv. 450:303–310. 2007. View Article : Google Scholar : PubMed/NCBI
52	Wang Z, He YL, Cai SR, Zhan WH, Li ZR, Zhu BH, Chen CQ, Ma JP, Chen ZX, Li W, et al: Expression and prognostic impact of PRL-3 in lymph node metastasis of gastric cancer: Its molecular mechanism was investigated using artificial microRNA interference. Int J Cancer. 123:1439–1447. 2008. View Article : Google Scholar : PubMed/NCBI
53	Xu W, Yang Z, Zhou SF and Lu N: Posttranslational regulation of phosphatase and tensin homolog (PTEN) and its functional impact on cancer behaviors. Drug Des Devel Ther. 8:1745–1751. 2014. View Article : Google Scholar : PubMed/NCBI
54	Bononi A and Pinton P: Study of PTEN subcellular localization. Methods. 77–78:92–103. 2015. View Article : Google Scholar
55	Milella M, Falcone I, Conciatori F, Cesta Incani U, Del Curatolo A, Inzerilli N, Nuzzo CM, Vaccaro V, Vari S, Cognetti F, et al: PTEN: Multiple functions in human malignant tumors. Front Oncol. 5:242015. View Article : Google Scholar : PubMed/NCBI
56	Su Z, Yang Z, Xu Y, Chen Y and Yu Q: Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer. 14:482015. View Article : Google Scholar : PubMed/NCBI
57	Khasigov PZ, Podobed OV, Gracheva TS, Salbiev KD, Grachev SV and Berezov TT: Role of matrix metalloproteinases and their inhibitors in tumor invasion and metastasis. Biochemistry. 68:711–717. 2003.PubMed/NCBI
58	Willems L, Tamburini J, Chapuis N, Lacombe C, Mayeux P and Bouscary D: PI3K and mTOR signaling pathways in cancer: New data on targeted therapies. Curr Oncol Rep. 14:129–138. 2012. View Article : Google Scholar : PubMed/NCBI
59	Ortega-Molina A and Serrano M: PTEN in cancer, metabolism, and aging. Trends Endocrinol Metab. 24:184–189. 2013. View Article : Google Scholar
60	Carnero A, Blanco-Aparicio C, Renner O, Link W and Leal JF: The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets. 8:187–198. 2008. View Article : Google Scholar : PubMed/NCBI