m6A RNA methylation-mediated upregulation of HLF promotes intrahepatic cholangiocarcinoma progression by regulating the FZD4/β-catenin signaling pathway

被引：16

作者：

Xiang, Daimin ^{[1
,2
,3
]}

Gu, Mingye ^{[1
,2
]}

Liu, Junyu ^{[2
]}

Dong, Wei ^{[4
]}

Yang, Zhishi ^{[5
]}

Wang, Kui ^{[5
,7
]}

Fu, Jing ^{[2
,3
]}

Wang, Hongyang ^{[1
,2
,3
,6
]}

机构：

[1] Shanghai Jiao Tong Univ, Renji Hosp, Shanghai Canc Inst, State Key Lab Oncogenes & Related Genes,Sch Med, Shanghai 200127, Peoples R China

[2] Naval Mil Med Univ, Int Cooperat Lab Signal Transduct, Minist Educ Key Lab Signaling Regulat & Targeting, Shanghai Key Lab Hepatobiliary Tumor Biol,Affiliat, Shanghai 200438, Peoples R China

[3] Natl Ctr Liver Canc, Shanghai, Peoples R China

[4] Naval Mil Med Univ, Affiliated Hosp 3, Dept Pathol, Shanghai 200438, Peoples R China

[5] Naval Mil Med Univ, Affiliated Hosp 3, Dept Hepat Surg, Shanghai 200438, Peoples R China

[6] Shanghai Jiao Tong Univ, Renji Hosp, Shanghai Canc Inst, Sch Med, 2117 Xietu Rd, Shanghai 200127, Peoples R China

[7] Naval Mil Med Univ, Affiliated Hosp 3, Dept Hepat Surg, 225 Changhai Rd, Shanghai 200438, Peoples R China

来源：

CANCER LETTERS | 2023年 / 560卷

基金：

中国国家自然科学基金;

关键词：

Intrahepatic cholangiocarcinoma; Cancer stem cells; HLF; m6A; FZD4; -catenin; HEPATOCELLULAR-CARCINOMA METASTASIS; CANCER; FOXQ1; DIAGNOSIS; FUSION; GENE; E2A;

D O I：

10.1016/j.canlet.2023.216144

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Hepatic leukemia factor (HLF) is aberrantly expressed in human malignancies. However, its role in regulating intrahepatic cholangiocarcinoma (ICC) remains unclear. This study aimed to define the role of HLF in ICC progression. Here, we showed that HLF expression is upregulated in ICC and predicts the poor prognosis in patients. Mechanistically, HLF activation in ICC is mediated by METTL3-dependent m6A methylation of the HLF mRNA. As per the results from the loss-or gain-of-function experiments, HLF promoted the self-renewal, tumorigenicity, proliferation and metastasis of ICC cells. RNA-seq and CUT&Tag analyses showed that frizzled-4 (FZD4) and forkhead box Q1 (FOXQ1) are target genes of HLF. Moreover, FOXQ1 transcriptionally activates METTL3 expression, forming a positive feedback loop, which subsequently activates WNT/beta-catenin signaling and downstream tumor stemness. Furthermore, HLF expression was positively correlated with METTL3, IGF2BP3, FZD4 and FOXQ1 expression in ICC tissues in a large ICC cohort. The combined IHC panels exhibited a better prognostic value for patients with ICC than any of these components alone. In conclusions, these findings demonstrated that the METTL3/HLF/FOXQ1 regulatory circuit drove FZD4-mediated WNT/ beta-catenin activation in ICC progression, suggesting that targeting this axis could be novel therapeutic strategy for ICC.

引用

页数：18