Tang Liping, Zhu Shasha, Peng Weiyan, Yin Xuedong, Tan Cui, Yang Yaying
Department of Gastroenterology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
The Center for Clinical Molecular Medical Detection, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
PeerJ. 2021 Feb 2;9:e10810. doi: 10.7717/peerj.10810. eCollection 2021.
Mitogen-activated protein kinase 10 () is a member of the c-jun N-terminal kinases () subgroup in the MAPK superfamily, and was proposed as a tumor suppressor inactivated epigenetically. Its role in hepatocellular carcinoma (HCC) has not yet been illustrated. We aimed to investigate the expression and epigenetic regulation of as well as its clinical significance in HCC.
was expressed in almost all the normal tissues including liver, while we found that the protein expression of MAPK10 was significantly downregulated in clinical samples of HCC patients compared with these levels in adjacent normal tissues (29/46, < 0.0001). Clinical significance of MAPK10 expression was then assessed in a cohort of 59 HCC cases, which indicated its negative expression was significantly correlated with advanced tumor stage ( = 0.001), more microsatellite nodules ( = 0.025), higher serum AFP ( = 0.001) and shorter overall survival time of HCC patients. Methylation was further detected in 58% of the HCC cell lines we tested and in 66% of primary HCC tissues by methylation-specific PCR (MSP), which was proved to be correlated with the silenced or downregulated expression of . To get the mechanisms more clear, the transcriptional silencing of was reversed by pharmacological demethylation, and ectopic expression of in silenced HCC cell lines significantly inhibited the colony formation ability, induced apoptosis, or enhanced the chemosensitivity of HCC cells to 5-fluorouracil.
appears to be a functional tumor suppressor gene frequently methylated in HCC, which could be a valuable biomarker or a new diagnosis and therapy target in a clinical setting.
丝裂原活化蛋白激酶10（MAPK10）是MAPK超家族中c-jun氨基末端激酶（JNK）亚组的成员，被认为是一种因表观遗传失活的肿瘤抑制因子。其在肝细胞癌（HCC）中的作用尚未阐明。我们旨在研究MAPK10在HCC中的表达、表观遗传调控及其临床意义。
MAPK10在包括肝脏在内的几乎所有正常组织中均有表达，而我们发现与相邻正常组织相比，HCC患者临床样本中MAPK10的蛋白表达显著下调（29/46，P<0.0001）。随后在59例HCC病例队列中评估了MAPK10表达的临床意义，结果表明其阴性表达与肿瘤晚期（P = 0.001）、更多微卫星结节（P = 0.025）、更高血清甲胎蛋白（P = 0.001）以及HCC患者更短的总生存时间显著相关。通过甲基化特异性PCR（MSP）在我们检测的58%的HCC细胞系和66%的原发性HCC组织中进一步检测到甲基化，这被证明与MAPK10的沉默或表达下调相关。为了更清楚地了解机制，通过药物去甲基化逆转了MAPK10的转录沉默，并且在沉默的HCC细胞系中异位表达MAPK10显著抑制了集落形成能力、诱导了凋亡或增强了HCC细胞对5-氟尿嘧啶的化疗敏感性。
MAPK10似乎是一个在HCC中频繁甲基化的功能性肿瘤抑制基因，在临床环境中可能是一个有价值的生物标志物或新的诊断和治疗靶点。
