Despite considerable advances in gastrectomy and chemotherapy, the prognosis of gastric cancer (GC) has not noticeably improved due to lymph node or distant metastases. P21-activated serine/threonine kinase 4 (Pak4) plays an important role in cell morphology and cytoskeletal reorganization—both prerequisite steps for cell migration. However, it is still unclear if activated Pak4 (p-Pak4) is related to prognosis in GC patients. In our study, the level of p-Pak4 in 95 GC tissue specimens was examined by immunohistochemistry (IHC). We observed significant correlation between the level of p-Pak4 and grosstype (advanced stage GC vs. early stage GC, P = 0.04). Moreover, GC patients with higher p-Pak4 levels had a poorer prognosis than those with lower p-Pak4 levels (17 vs. 38 months, P = 0.001). Multivariate analysis showed that high phosphorylation level of Pak4, advanced stage GC, and lymph node metastasis were independent prognostic factors for GC patients (p-Pak4, P = 0.026; advanced stage GC, P = 0.030; lymph node metastasis, P = 0.016). In addition, in vitro assays indicated that knockdown of Pak4 accompanied with decreased p-Pak4, inhibited cell migration via downregulation of the traditional downstream signaling pathways of Pak4, LIMK1, and cofilin. In conclusion, this report reveals that high level of p-Pak4 correlates with poor prognosis in GC, thereby suggesting that p-Pak4 might be a potential prognostic marker for GC.
p-Pak4 Gastric cancer Prognosis Migration
This is a preview of subscription content, log in to check access.
Conflicts of interest
This work was supported by the National Science and Technology Major Project (No. 2013ZX09303002) and the National Natural Science Foundation of China (Nos. 81270036, 81472193, 81372546, 81372485).
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer J int du Dancer. 2010;127(12):2893–917. doi:10.1002/ijc.25516.CrossRefGoogle Scholar
Ye Y, Zhou X, Li X, Tang Y, Sun Y, Fang J. Inhibition of epidermal growth factor receptor signaling prohibits metastasis of gastric cancer via downregulation of MMP7 and MMP13. Tumour Biol: J Int Soc Oncodevelopmental Biol Med. 2014;35(11):10891–6. doi:10.1007/s13277-014-2383-1.CrossRefGoogle Scholar
Kim JH, Kim HN, Lee KT, Lee JK, Choi SH, Paik SW, et al. Gene expression profiles in gallbladder cancer: the close genetic similarity seen for early and advanced gallbladder cancers may explain the poor prognosis. Tumour Biol: J Int Soc Oncodevelopmental Biol Med. 2008;29(1):41–9. doi:10.1159/000132570.CrossRefGoogle Scholar
Zhang J, Wang J, Guo Q, Wang Y, Zhou Y, Peng H, et al. LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells. Cancer Lett. 2012;317(1):24–32. doi:10.1016/j.canlet.2011.11.007.CrossRefPubMedGoogle Scholar
Mak GW, Chan MM, Leong VY, Lee JM, Yau TO, Ng IO, et al. Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis. Cancer Res. 2011;71(8):2949–58. doi:10.1158/0008-5472.CAN-10-4046.CrossRefPubMedGoogle Scholar
Lu W, Xia YH, Qu JJ, He YY, Li BL, Lu C, et al. p21-activated kinase 4 regulation of endometrial cancer cell migration and invasion involves the ERK1/2 pathway mediated MMP-2 secretion. Neoplasma. 2013;60(5):493–503. doi:10.4149/neo_2013_064.CrossRefPubMedGoogle Scholar
Ahn HK, Jang J, Lee J, Se Hoon P, Park JO, Park YS, et al. P21-activated kinase 4 overexpression in metastatic gastric cancer patients. Transl Oncol. 2011;4(6):345–9.CrossRefPubMedPubMedCentralGoogle Scholar