Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Cancer Sci. 2018 May;109(5):1414-1427. doi: 10.1111/cas.13598.
Protein arginine methyltransferases (PRMT) catalyze protein arginine methylation and play an important role in many biological processes. Aberrant PRMT expression in tumor cells has been documented in several common cancer types; however, its precise contribution to hepatocellular carcinoma (HCC) cell invasion and metastasis is not fully understood. In this study, we identified a new oncogene, PRMT9, whose overexpression strongly promotes HCC invasion and metastasis. PRMT9 expression was detected more frequently in HCC tissues than in adjacent noncancerous tissues. PRMT9 overexpression was significantly correlated with hepatitis B virus antigen (HBsAg) status, vascular invasion, poor tumor differentiation and advanced TNM stage. Patients with higher PRMT9 expression had a shorter survival time and higher recurrence rate. PRMT9 expression was an independent and significant risk factor for survival after curative resection. Functional studies demonstrated that PRMT9 increased HCC cell invasion and lung metastasis. Knocking down PRMT9 with short hairpin RNA (shRNA) inhibited HCC cell invasion. Further investigations found that PRMT9 increased cell migration and invasion through epithelial-mesenchymal transition (EMT) by regulating Snail expression via activation of the PI3K/Akt/GSK-3β/Snail signaling pathway. In clinical HCC samples, PRMT9 expression was positively associated with Snail expression and was negatively associated with E-cadherin expression. In conclusion, our study demonstrated that PRMT9 is an oncogene that plays an important role in HCC invasion and metastasis through EMT by regulating Snail expression via activation of the PI3K/Akt/GSK-3β/Snail signaling pathway. Thus, PRMT9 may serve as a candidate prognostic biomarker and a potential therapeutic target.
蛋白质精氨酸甲基转移酶（PRMT）催化蛋白质精氨酸甲基化，在许多生物过程中发挥重要作用。几种常见癌症类型的肿瘤细胞中已经发现了异常的 PRMT 表达；然而，其对肝细胞癌（HCC）细胞侵袭和转移的确切贡献尚不完全清楚。在这项研究中，我们鉴定了一种新的癌基因 PRMT9，其过表达强烈促进 HCC 的侵袭和转移。PRMT9 的表达在 HCC 组织中比在相邻的非癌组织中更频繁地被检测到。PRMT9 的过表达与乙型肝炎病毒抗原（HBsAg）状态、血管侵犯、肿瘤分化不良和晚期 TNM 分期显著相关。PRMT9 表达较高的患者生存时间较短，复发率较高。PRMT9 表达是根治性切除术后生存的独立且重要的危险因素。功能研究表明，PRMT9 增加了 HCC 细胞的侵袭和肺转移。用短发夹 RNA（shRNA）敲低 PRMT9 抑制了 HCC 细胞的侵袭。进一步的研究发现，PRMT9 通过激活 PI3K/Akt/GSK-3β/Snail 信号通路调节 Snail 的表达，通过上皮-间质转化（EMT）增加细胞迁移和侵袭。在临床 HCC 样本中，PRMT9 的表达与 Snail 的表达呈正相关，与 E-钙黏蛋白的表达呈负相关。总之，我们的研究表明，PRMT9 是一种癌基因，通过激活 PI3K/Akt/GSK-3β/Snail 信号通路调节 Snail 的表达，通过 EMT 在 HCC 的侵袭和转移中发挥重要作用。因此，PRMT9 可能作为候选预后生物标志物和潜在的治疗靶点。
