ALKBH5/MAP3K8 axis regulates PD-L1+macrophage infiltration and promotes hepatocellular carcinoma progression

作者全名："You, Yu; Wen, Diguang; Zeng, Lu; Lu, Jiao; Xiao, Xiao; Chen, Yucheng; Song, Hua; Liu, Zuojin"

作者地址："[You, Yu; Wen, Diguang; Lu, Jiao; Chen, Yucheng; Song, Hua; Liu, Zuojin] Chongqing Med Univ, Affiliated Hosp 2, Hepatobiliary Surg Dept, Chongqing 400010, Peoples R China; [Zeng, Lu] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing 400010, Peoples R China; [Xiao, Xiao] Chongqing Univ Cent Hosp, Chongqing Emergency Med Ctr, Dept Gastroenterol, Chongqing 400010, Peoples R China"

通信作者："Liu, ZJ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Hepatobiliary Surg Dept, Chongqing 400010, Peoples R China."

来源：INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000836455100002

JCR分区：Q1

影响因子：9.2

年份：2022

卷号：18

期号：13

开始页：5001

结束页：5018

文献类型：Article

关键词：M6A; Hypoxia; Tumor-associated macrophages; Immune microenvironment; PD-L1

摘要："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."

基金机构："National Science Foundation of China [82070678, 81702357]; China Postdoctoral Science Foundation [2018M643424]; Chen Xiao-ping foundation for the development of science and technology [CXPJJH12000001-2020330]; Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University; Chongqing Natural Science Foundation [cstc2019jcyj-zdxmX0027]; Basic research and frontier exploration project of Yuzhong District Science and Technology Commission of Chongqing [20180148]"

基金资助正文："This project was supported by the National Science Foundation of China (No. 82070678, 81702357), China Postdoctoral Science Foundation Grant (No. 2018M643424), Chen Xiao-ping foundation for the development of science and technology (No. CXPJJH12000001-2020330), Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University and Chongqing Natural Science Foundation (cstc2019jcyj-zdxmX0027). Basic research and frontier exploration project of Yuzhong District Science and Technology Commission of Chongqing (Project No. 20180148)."