CCL3 Secreted by Hepatocytes Promotes the Metastasis of Intrahepatic Cholangiocarcinoma by VIRMA-mediated N6-methyladenosine (mA) Modification

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2023 Jan 23

PMID 36691046

Authors

Shurui Zhou

Kege Yang

Shaojie Chen

Guoda Lian

Yuzhou Huang

Hanming Yao

Yue Zhao

Kaihong Huang

Dong Yin

Haoming Lin

Yaqing Li

Affiliations

Soon will be listed here.

Abstract

Background: Intrahepatic cholangiocarcinoma (ICC) is a malignant disease characterized by onset occult, rapid progression, high relapse rate, and high mortality. However, data on how the tumor microenvironment (TME) regulates ICC metastasis at the transcriptomic level remains unclear. This study aimed to explore the mechanisms and interactions between hepatocytes and ICC cells.

Methods: We analyzed the interplay between ICC and liver microenvironment through cytokine antibody array analysis. Then we investigated the role of N6-methyladenosine (mA) modification and the downstream target in vitro, in vivo experiments, and in clinical specimens.

Results: Our study demonstrated that cytokine CCL3, which is secreted by hepatocytes, promotes tumor metastasis by regulating mA modification via vir-like mA methyltransferase associated (VIRMA) in ICC cells. Moreover, immunohistochemical analyses showed that VIRMA correlated with poor outcomes in ICC patients. Finally, we confirmed both in vitro and in vivo that CCL3 could activate VIRMA and its critical downstream target SIRT1, which fuels tumor metastasis in ICC.

Conclusions: In conclusion, our results enhanced our understanding of the interaction between hepatocytes and ICC cells, and revealed the molecular mechanism of the CCL3/VIRMA/SIRT1 pathway via mA-mediated regulation in ICC metastasis. These studies highlight potential targets for the diagnosis, treatment, and prognosis of ICC.

Citing Articles

m6A epitranscriptomic modification in hepatocellular carcinoma: implications for the tumor microenvironment and immunotherapy.

Liu F, Liu Q, Li X, Wang Y, Cao R, Zhang S Front Immunol. 2025; 16:1538658.

PMID: 40034695 PMC: 11873077. DOI: 10.3389/fimmu.2025.1538658.

Liver Metastasis in Cancer: Molecular Mechanisms and Management.

Xu W, Xu J, Liu J, Wang N, Zhou L, Guo J MedComm (2020). 2025; 6(3):e70119.

PMID: 40027151 PMC: 11868442. DOI: 10.1002/mco2.70119.

EBV-Induced LINC00944: A Driver of Oral Cancer Progression and Influencer of Macrophage Differentiation.

Srisathaporn S, Ekalaksananan T, Heawchaiyaphum C, Aromseree S, Maranon D, Altina N Cancers (Basel). 2025; 17(3).

PMID: 39941858 PMC: 11815735. DOI: 10.3390/cancers17030491.

N-acetyltransferase 10 affects the proliferation of intrahepatic cholangiocarcinoma and M2-type polarization of macrophages by regulating C-C motif chemokine ligand 2.

Cai T, Dai J, Lin Y, Bai Z, Li J, Meng W J Transl Med. 2024; 22(1):875.

PMID: 39350174 PMC: 11440763. DOI: 10.1186/s12967-024-05664-z.

Landscape of mA RNA methylation regulators in liver cancer and its therapeutic implications.

Zhao J, Li G, Lu X, Zhu L, Gao Q Front Pharmacol. 2024; 15:1376005.

PMID: 38545555 PMC: 10965734. DOI: 10.3389/fphar.2024.1376005.

References

Razumilava N, Gores G . Cholangiocarcinoma. Lancet. 2014; 383(9935):2168-79. PMC: 4069226. DOI: 10.1016/S0140-6736(13)61903-0. View

Meyer K, Jaffrey S . The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat Rev Mol Cell Biol. 2014; 15(5):313-26. PMC: 4393108. DOI: 10.1038/nrm3785. View

Miranda-Goncalves V, Lobo J, Guimaraes-Teixeira C, Barros-Silva D, Guimaraes R, Cantante M . The component of the mA writer complex VIRMA is implicated in aggressive tumor phenotype, DNA damage response and cisplatin resistance in germ cell tumors. J Exp Clin Cancer Res. 2021; 40(1):268. PMC: 8390281. DOI: 10.1186/s13046-021-02072-9. View

Ong A, Ramasamy T . Role of Sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming. Ageing Res Rev. 2018; 43:64-80. DOI: 10.1016/j.arr.2018.02.004. View

Chang G, Leu J, Ma L, Xie K, Huang S . Methylation of RNA N-methyladenosine in modulation of cytokine responses and tumorigenesis. Cytokine. 2018; 118:35-41. DOI: 10.1016/j.cyto.2018.06.018. View

Chen M, Wei L, Law C, Tsang F, Shen J, Cheng C . RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology. 2017; 67(6):2254-2270. DOI: 10.1002/hep.29683. View

Lan T, Li H, Zhang D, Xu L, Liu H, Hao X . KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3. Mol Cancer. 2019; 18(1):186. PMC: 6921542. DOI: 10.1186/s12943-019-1106-z. View

Gentilini A, Pastore M, Marra F, Raggi C . The Role of Stroma in Cholangiocarcinoma: The Intriguing Interplay between Fibroblastic Component, Immune Cell Subsets and Tumor Epithelium. Int J Mol Sci. 2018; 19(10). PMC: 6213545. DOI: 10.3390/ijms19102885. View

Chen X, Xu M, Xu X, Zeng K, Liu X, Pan B . METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer. Mol Cancer. 2020; 19(1):106. PMC: 7298962. DOI: 10.1186/s12943-020-01220-7. View

10.

Miller J, Fink A, Banagis J, Nagashima H, Subramanian M, Lee C . Sirtuin activation targets IDH-mutant tumors. Neuro Oncol. 2020; 23(1):53-62. PMC: 7850026. DOI: 10.1093/neuonc/noaa180. View

11.

Wen J, Lv R, Ma H, Shen H, He C, Wang J . Zc3h13 Regulates Nuclear RNA mA Methylation and Mouse Embryonic Stem Cell Self-Renewal. Mol Cell. 2018; 69(6):1028-1038.e6. PMC: 5858226. DOI: 10.1016/j.molcel.2018.02.015. View

12.

Roundtree I, Evans M, Pan T, He C . Dynamic RNA Modifications in Gene Expression Regulation. Cell. 2017; 169(7):1187-1200. PMC: 5657247. DOI: 10.1016/j.cell.2017.05.045. View

13.

Chow M, Luster A . Chemokines in cancer. Cancer Immunol Res. 2014; 2(12):1125-31. PMC: 4258879. DOI: 10.1158/2326-6066.CIR-14-0160. View

14.

Fabris L, Sato K, Alpini G, Strazzabosco M . The Tumor Microenvironment in Cholangiocarcinoma Progression. Hepatology. 2020; 73 Suppl 1:75-85. PMC: 7714713. DOI: 10.1002/hep.31410. View

15.

Zhang Z, Hong D, Nam S, Kim J, Paik Y, Joh J . SIRT1 regulates oncogenesis via a mutant p53-dependent pathway in hepatocellular carcinoma. J Hepatol. 2014; 62(1):121-30. DOI: 10.1016/j.jhep.2014.08.007. View

16.

Qian J, Gao J, Sun X, Cao M, Shi L, Xia T . KIAA1429 acts as an oncogenic factor in breast cancer by regulating CDK1 in an N6-methyladenosine-independent manner. Oncogene. 2019; 38(33):6123-6141. DOI: 10.1038/s41388-019-0861-z. View

17.

Banales J, Marin J, Lamarca A, Rodrigues P, Khan S, Roberts L . Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020; 17(9):557-588. PMC: 7447603. DOI: 10.1038/s41575-020-0310-z. View

18.

de Palma M, Biziato D, Petrova T . Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017; 17(8):457-474. DOI: 10.1038/nrc.2017.51. View

19.

Hui L, Chen Y . Tumor microenvironment: Sanctuary of the devil. Cancer Lett. 2015; 368(1):7-13. DOI: 10.1016/j.canlet.2015.07.039. View

20.

Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W . FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling. Cancer Res. 2016; 76(14):4124-35. DOI: 10.1158/0008-5472.CAN-15-2973. View