Lactic acidosis promotes aggressive features of cholangiocarcinoma cells via upregulating ALDH1A3 expression through EGFR axis
Lactic acidosis promotes aggressive features of cholangiocarcinoma cells via upregulating ALDH1A3 expression through EGFR axis
复制标题
DOI：
10.1016/j.lfs.2022.120648
复制
发表时间：
2022-05-25
期刊：
影响因子：
6.1
通讯作者：
Wongkham，Sopit
中科院分区：
文献类型：
--
作者：
Thamrongwaranggoon，Ubonrat;Detarya，Marutpong;Wongkham，Sopit
肿瘤微环境中产生的乳酸酸中毒（LA）促进肿瘤的转移和耐药。本研究旨在阐明LA对乙醛脱氢酶1A 3（ALDH 1A 3）在促进胆管癌（CCA）细胞株侵袭性和吉西他滨耐药中的作用及其机制。主要方法利用GEO数据库分析ALDH 1A 3在CCA组织中的表达及其临床意义。本文研究了人CCA细胞系KKU-213 A-LA和KKU-213 B-LA在LA培养基中的生长情况，并与其亲本细胞在正常培养基中的生长情况进行了比较。确定侵袭性特征-增殖、集落形成、迁移、侵袭和吉西他滨反应。采用实时荧光定量PCR和Western blotting分析ALDH 1A 3、EGFR及其下游效应因子的表达。LA细胞ALDH 1A 3 mRNA和蛋白表达增加。通过siRNA减弱ALDH 1A 3表达显著降低LA细胞和吉西他滨抗性细胞的细胞增殖、集落形成、迁移、侵袭和吉西他滨抗性。通过Erk和STAT 3的EGF/EGFR信号传导被固定为参与LA细胞中ALDH 1A 3表达的诱导。TCGA数据集的转录组学分析支持LDHA、EGFR和ALDH 1A 3在几种肿瘤组织中的相关性，显著性乳酸酸中毒上调EGFR和ALDH 1A 3的表达，导致CCA细胞的侵袭性。EGFR/ALDH 1A 3轴可能成为根除转移性CCA的新的治疗靶点。
AimsLactic acidosis (LA) generated in tumor microenvironment promotes tumor metastasis and drug resistance. This study aimed to demonstrate the impacts and the mechanisms of LA on aldehyde dehydrogenase1A3 (ALDH1A3) in promoting aggressiveness and gemcitabine resistance in cholangiocarcinoma (CCA) cell lines. The clinical relevance and the molecular pathway related to the upregulation of ALDH1A3 in LA cells will be revealed.Main methodsALDH1A3 expression and its clinical significances in CCA tissues were analyzed using the GEO databases. Human CCA cell lines, KKU-213A-LA and KKU-213B-LA maintained in the LA medium were studied and compared with its parental cells cultured in normal medium. Aggressive features—proliferation, colony formation, migration, invasion, and gemcitabine response were determined. Expression of ALDH1A3, EGFR and the downstream effectors were analyzed using real-time PCR and Western blotting.Key findingsALDH1A3 was upregulated in patient CCA tissues and correlated with LDHA and shorter survival of CCA patients. mRNA and protein of ALDH1A3 were increased in LA cells. Attenuation of ALDH1A3 expression by siRNA significantly reduced cell proliferation, colony formation, migration, invasion, and gemcitabine resistance of LA cells, and gemcitabine resistant cells. The EGF/EGFR signaling via Erk and STAT3 was pinned to be involved in the induction of ALDH1A3 expression in LA cells. The transcriptomic analysis from TCGA dataset supported the links between LDHA, EGFR and ALDH1A3 in several tumor tissues.SignificanceLactic acidosis upregulated EGFR and ALDH1A3 expression, leading to the aggressiveness of CCA cells. The EGFR/ALDH1A3 axis could be a novel therapeutic target to eradicate metastatic CCA.