Zhang Xiu-Ping, Jiang Ya-Bo, Zhong Cheng-Qian, Ma Ning, Zhang Er-Bin, Zhang Fan, Li Jing-Jing, Deng Yue-Zhen, Wang Kang, Xie Dong, Cheng Shu-Qun
Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
LongYan First Hospital, Affiliated to Fujian Medical University, FuJian, China.
Cell Physiol Biochem. 2018;47(4):1643-1654. doi: 10.1159/000490983. Epub 2018 Jun 23.
BACKGROUND/AIMS: Although it has been widely accepted that protein arginine methyltransferase 1 (PRMT1) is a cancer-promoting gene in various cancers, the mechanism of PRMT1 in hepatocellular carcinoma (HCC) requires more exploration. This study aimed to investigate the role of PRMT1 in HCC growth and metastasis.
We compared PRMT1 expression and clinicopathological characteristics using paired HCC and adjacent noncancerous liver tissues from 210 patients and immunohistochemistry analyses. Cell proliferation, colony formation and migration were determined in HCC cell lines with PRMT1 overexpression or downregulation through MTT, crystal violet and Boyden chamber assays. Tumour growth was monitored in a xenograft model, and intrahepatic metastasis models were established.
PRMT1 expression was greatly increased in clinical HCC samples and strongly associated with poor prognosis and recurrence; PRMT1 expression was also positively correlated with microvascular invasion (P = 0.024), tumour differentiation (P = 0.014), tumour size (P = 0.002), and portal vein tumour thrombus (PVTT) (P = 0.028). Cell proliferation, colony formation and migration in vitro were enhanced by PRMT1 upregulation and decreased by PRMT1 downregulation in HCC cell lines. Moreover, low PRMT1 expression resulted in slow tumour growth and decreased tumour weight in vivo, as well as tumour metastasis. These phenotypes were associated with STAT3 signalling pathway activation. Cryptotanshinone, a STAT3 inhibitor, inhibited STAT3 phosphorylation and reversed the HCC phenotype of PRMT1 expression.
We revealed a significant role for PRMT1 in HCC progression and metastasis in vitro and in vivo via STAT3 signalling pathway activation. PRMT1 may be a potential novel prognostic biomarker and new therapeutic target for HCC.
背景/目的：尽管蛋白质精氨酸甲基转移酶1（PRMT1）在多种癌症中作为促癌基因已被广泛接受，但其在肝细胞癌（HCC）中的作用机制仍需进一步探索。本研究旨在探讨PRMT1在HCC生长和转移中的作用。
我们使用210例患者的配对HCC和癌旁非癌肝组织，通过免疫组织化学分析比较PRMT1表达与临床病理特征。通过MTT、结晶紫和Boyden小室试验，检测PRMT1过表达或下调的HCC细胞系中的细胞增殖、集落形成和迁移。在异种移植模型中监测肿瘤生长，并建立肝内转移模型。
PRMT1在临床HCC样本中的表达显著增加，且与预后不良和复发密切相关；PRMT1表达还与微血管侵犯（P = 0.024）、肿瘤分化（P = 0.014）、肿瘤大小（P = 0.002）和门静脉癌栓（PVTT）（P = 0.028）呈正相关。在HCC细胞系中，PRMT1上调增强了体外细胞增殖、集落形成和迁移，而PRMT1下调则降低了这些指标。此外，低PRMT1表达导致体内肿瘤生长缓慢、肿瘤重量减轻以及肿瘤转移减少。这些表型与STAT3信号通路激活有关。隐丹参酮作为一种STAT3抑制剂，可抑制STAT3磷酸化并逆转PRMT1表达的HCC表型。
我们揭示了PRMT1通过激活STAT3信号通路在体外和体内HCC进展和转移中发挥的重要作用。PRMT1可能是HCC潜在的新型预后生物标志物和新的治疗靶点。
