Mechanisms of GOLPH3 Associated with the Progression of Gastric Cancer: A Preliminary Study

Abstract

Study DesignTo investigate the specific mechanisms by which Golgi phosphoprotein 3 (GOLPH3) affects the progression of gastric cancer and to explore its clinical significance.MethodsImmunohistochemical analysis was used to evaluate the correlations between GOLPH3, phosphorylated mTOR (p-mTOR), phosphorylated Akt (p-Akt), phosphorylated p70S6 (p-p70S6), phosphorylated 4E-BP1 (p-4E-BP1) and the clinicopathological features of gastric cancer. The mRNA expression levels of GOLPH3, mTOR, Akt, p70S6 and 4E-BP1 in gastric cancer, carcinoma-adjacent and paired normal tissue were analyzed using RT-PCR. Western blotting was used to determine the protein expression of GOLPH3, p-mTOR, p-Akt, p-p70S6 and p-4E-BP1 in tissues.ResultsHigh expression protein levels of GOLPH3, p-AKT, p-mTOR, p70S6, p-4E-BP1 were positively associated with histological grade (p<0.05), depth of invasion (p<0.05), distant metastasis (p<0.05) and lymph node involvement (p<0.05). Compared with carcinoma-adjacent and paired normal tissues, the mRNA expression levels of GOLPH3, AKT, mTOR, p70S6 and 4EBP1 in gastric cancer tissues were significantly higher. The protein expression levels of GOLPH3, p-AKT, p-mTOR, p-p70S6 and p-4E-BP1 in gastric cancer tissues were also significantly higher than in carcinoma-adjacent and paired normal tissues. A strong positive correlation was observed between GOLPH3, p-mTOR, p-p70S6 and p-4EBP1 expression (r = 0.410, 0.303 and 0.276, respectively, p<0.05), but no significant correlation between the expression of GOLPH3 and p-Akt was observed.ConclusionsThe GOPLH3 expression level is highly correlated with Akt/mTOR signaling in human gastric cancer samples. GOLPH3 combined with Akt/mTOR signaling activation may play an important role in the development, differentiation, invasion and metastasis of gastric cancer.

MicroRNA-134 suppresses cell proliferation in gastric cancer cells via targeting of GOLPH3

“…Similarly, Murayama et al reported that p-mTOR expression was positively correlated with GC tumor invasion and tumor stage (31). In addition, a preliminary study revealed that GOLPH3 was positively correlated with Akt/mTOR activation in GC (18). In line with these studies, we showed in the present study that the phosphorylation of AKT, mTOR and mTOR downstream substrate protein S6K were impaired by miR-134 overexpression, while overexpression of GOLPH3 restored this effect caused by miR-134, suggesting that miR-134 regulated this AKT/mTOR/S6K signaling pathway via a GOLPH3-dependent mechanism.…”

“…4A). Moreover, a recent study showed that the mRNA level of GOLPH3 is upregulated in GC tissue and is positively associated with cell proliferation (18). Given this evidence and the observed function in miR-134-overexpressing cell lines and mice, we speculated that GOLPH3 was a target of miR-134.…”

Oncogenic Roles of GOLPH3 in the Physiopathology of Cancer

“…An increasing number of papers has shown that GOLPH3 drives cancer in several other solid tumors such as Neuroblastoma (NB) [42], Non-Small Cell Lung Cancer (NSLC) [89], epithelial ovarian carcinoma [90], prostate cancer [91,92], gastric cancer [93], and hepatocellular carcinoma [94,95] ( Figure 2). Recent reports indicate that GOLPH3 overexpression can be used as a positive biomarker for tumor progression and poor survival in these cancer types [89][90][91][92][93][94][95][96][97][98]. Experimental data in cancer cell lines or in nude mice revealed the role of GOLPH3 in cell proliferation, metastasis formation and angiogenesis ( Figure 2).…”

GOLPH3 Links the Golgi, DNA Damage, and Cancer

“…Evidence of transformation by overexpression of GOLPH3 has been reported in MDA-MB-231 and MCF7 breast cancer cell lines (9–11), and U251 and U87 glioblastoma cell lines (12, 13). Frequent overexpression of GOLPH3 and correlation with poor prognosis have been reported in multiple tumor types including 58–72% of non-small cell lung cancers (14, 15), 52% of breast cancers (11), 70% of prostate cancers (16), 73% of pancreatic ductal adenocarcinomas (17), 65% of hepatocellular carcinomas (18, 19), 55–58% of gastric cancers (20, 21), 53% of renal cell carcinomas (22), 41–53% of glioblastomas (12, 23, 24), 49% of esophageal squamous carcinomas (25), and 45% of ovarian carcinomas (26, 27). Overexpression of GOLPH3 occurs frequently in rhabdomyosarcoma, and knockdown of GOLPH3 in rhabdomyosarcoma cell lines impairs cell proliferation (28).…”