Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Department of Gastroenterology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Int J Biol Sci. 2022 Aug 1;18(13):5001-5018. doi: 10.7150/ijbs.70149. eCollection 2022.
Hepatocellular carcinoma is one of the most common malignant tumors.M6A is a novel epigenetic modification that have been emerged as vital regulators for the progression of HCC. However, the regulatory role, clinical significance and the details of the modification, such as the impact on the local tumor environment, remain largely unclear. Our study showed that ALKBH5 was highly expressed in HCC and high ALKBH5 expression predicted a worse prognosis of HCC patients. Prediction of ALKBH5 function by tissue samples and single cell sequencing Gene Set Variation Analysis. Primary CD3 + T lymphocytes and bone marrow-derived macrophages were used to evaluate the effect of ALKBH5 on immune microenvironment. The results indicated that ALKBH5 promote HCC cell proliferation, metastasis and PD-L1+macrophage recruitment. Mechanistically the results showed that ALKBH5 regulates MAP3K8 expression in a m6A dependent manner which mediates the proliferation and metastasis of HCC cells. ALKBH5 also promotes the activation of JNK and ERK pathways through upregulating MAP3K8, thus regulating the expression of IL-8 and promoting macrophage recruitment. Taken together, these data show that ALKBH5 promotes HCC growth, metastasis and macrophage recruitment through ALKBH5/MAP3K8 axis and it may serve as a potential diagnostic marker and target for treatment of HCC patients.
肝细胞癌是最常见的恶性肿瘤之一。m6A 是一种新出现的表观遗传修饰，已成为 HCC 进展的重要调节剂。然而，其调节作用、临床意义以及修饰的细节（如对局部肿瘤微环境的影响）在很大程度上仍不清楚。我们的研究表明，ALKBH5 在 HCC 中高表达，高 ALKBH5 表达预示着 HCC 患者的预后更差。通过组织样本和单细胞测序基因集变异分析预测 ALKBH5 的功能。原代 CD3+T 淋巴细胞和骨髓来源的巨噬细胞用于评估 ALKBH5 对免疫微环境的影响。结果表明，ALKBH5 促进 HCC 细胞增殖、转移和 PD-L1+巨噬细胞募集。机制研究表明，ALKBH5 以 m6A 依赖的方式调节 MAP3K8 的表达，从而介导 HCC 细胞的增殖和转移。ALKBH5 还通过上调 MAP3K8 促进 JNK 和 ERK 通路的激活，从而调节 IL-8 的表达并促进巨噬细胞募集。综上所述，这些数据表明，ALKBH5 通过 ALKBH5/MAP3K8 轴促进 HCC 的生长、转移和巨噬细胞募集，它可能作为 HCC 患者的潜在诊断标志物和治疗靶点。
