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

Daimin Xiang; Mingye Gu; Junyu Liu; Wei Dong; Zhishi Yang; Kui Wang; Jing Fu; Hongyang Wang

doi:10.1016/j.canlet.2023.216144

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

Cancer Lett. 2023 Apr 28:560:216144. doi: 10.1016/j.canlet.2023.216144. Epub 2023 Mar 22.

Authors

Daimin Xiang¹, Mingye Gu², Junyu Liu³, Wei Dong⁴, Zhishi Yang⁵, Kui Wang⁶, Jing Fu⁷, Hongyang Wang⁸

Affiliations

¹ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Shanghai, China.
² State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China.
³ International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China.
⁴ Department of Pathology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China.
⁵ Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China.
⁶ Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China. Electronic address: wangkuiykl@163.com.
⁷ International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Shanghai, China. Electronic address: fujing@smmu.edu.cn.
⁸ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Shanghai, China. Electronic address: hywangk@vip.sina.com.

PMID: 36958694
DOI: 10.1016/j.canlet.2023.216144

Abstract

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/β-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/β-catenin activation in ICC progression, suggesting that targeting this axis could be novel therapeutic strategy for ICC.

Keywords: Cancer stem cells; FZD4/β-catenin; HLF; Intrahepatic cholangiocarcinoma; m6A.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bile Duct Neoplasms* / pathology
Bile Ducts, Intrahepatic / pathology
Cell Line, Tumor
Cholangiocarcinoma* / pathology
Forkhead Transcription Factors / metabolism
Frizzled Receptors / genetics
Humans
Methylation
Methyltransferases / metabolism
RNA, Messenger / metabolism
Up-Regulation
Wnt Signaling Pathway / genetics
beta Catenin / metabolism

Substances

beta Catenin
Forkhead Transcription Factors
FOXQ1 protein, human
Frizzled Receptors
FZD4 protein, human
Methyltransferases
METTL3 protein, human
RNA, Messenger
HLF protein, human
CTNNB1 protein, human