ARHGEF39 promotes gastric cancer cell proliferation and migration via Akt signaling pathway
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Dbl-family guanine nucleotide exchange factors (GEFs) can activate RhoGTPases by facilitating the exchange of GDP for GTP, the aberrant expression of which has been implicated in tumorigenicity and metastasis of human cancers. ARHGEF39, as a member of Dbl-family GEFs, was reported to be a potential oncogene in human hepatocellular carcinoma previously. However, the role of ARHGEF39 in gastric cancer (GC) remains unclear so far. In the current study, we demonstrated that ARHGEF39 expression was significantly upregulated in GC tissues compared with paired adjacent normal tissues by quantitative real-time PCR analysis. Functional analyses revealed that ARHGEF39 overexpression could promote proliferation, colony formation, and migration of GC cells in vitro, whereas ARHGEF39 knockdown markedly suppressed these phenotypes. Moreover, ARHGEF39 enhanced tumorigenicity and lung metastasis potential of GC cells in nude mice model. Mechanistically, we found that overexpressed ARHGEF39 significantly increased the phosphorylation level of Akt (p-Akt), and its effect on cell proliferation was attenuated by PI3K inhibitor LY294002. Thus, our findings suggest that ARHGEF39 may contribute to cell proliferation and migration in GC via a possible mechanism involving Akt signaling.
KeywordsARHGEF39 Gastric cancer Cell proliferation Migration Akt
This work was supported by the National Natural Science Foundation of China (No. 81302490).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 2.Ferro A, Peleteiro B, Malvezzi M, Bosetti C, Bertuccio P, Levi F, Negri E, La Vecchia C, Lunet N (2014) Worldwide trends in gastric cancer mortality (1980–2011), with predictions to 2015, and incidence by subtype. Eur J Cancer 50:1330–1344. doi: 10.1016/j.ejca.2014.01.029 CrossRefPubMedGoogle Scholar
- 3.De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, Trama A, Visser O, Brenner H, Ardanaz E, Bielska-Lasota M, Engholm G, Nennecke A, Siesling S, Berrino F, Capocaccia R, Group E-W (2014) Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE-5-a population-based study. Lancet Oncol 15:23–34. doi: 10.1016/S1470-2045(13)70546-1 CrossRefPubMedGoogle Scholar
- 12.Fernandez-Zapico ME, Gonzalez-Paz NC, Weiss E, Savoy DN, Molina JR, Fonseca R, Smyrk TC, Chari ST, Urrutia R, Billadeau DD (2005) Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis. Cancer Cell 7:39–49. doi: 10.1016/j.ccr.2004.11.024 CrossRefPubMedGoogle Scholar
- 13.Citterio C, Menacho-Marquez M, Garcia-Escudero R, Larive RM, Barreiro O, Sanchez-Madrid F, Paramio JM, Bustelo XR (2012) The rho exchange factors vav2 and vav3 control a lung metastasis-specific transcriptional program in breast cancer cells. Sci Signal 5:ra71. doi: 10.1126/scisignal.2002962 CrossRefPubMedGoogle Scholar
- 18.Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ, Kim YH, Ji J, Yeh TS, Button P, Sirzen F, Noh SH, investigators Ct (2012) Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 379:315–321. doi: 10.1016/S0140-6736(11)61873-4 CrossRefPubMedGoogle Scholar
- 19.Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K (2007) Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357:1810–1820. doi: 10.1056/NEJMoa072252 CrossRefPubMedGoogle Scholar
- 20.Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y (2011) Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol 29:4387–4393. doi: 10.1200/JCO.2011.36.5908 CrossRefPubMedGoogle Scholar