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Original Article | Open Access

The m6A writers regulated by the IL-6/STAT3 inflammatory pathway facilitate cancer cell stemness in cholangiocarcinoma

Hua Ye1,*, Tianqi Chen2,*, Zhancheng Zeng2,*, Bo He3, Qianqian Yang2, Qi Pan2, Yueqin Chen2, Wentao Wang2 ( )
Department of Hepatobiliary, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China

*These authors contributed equally to this work.

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Abstract

Objective

Investigation of the regulatory mechanisms of cell stemness in cholangiocarcinoma (CCA) is essential for developing effective therapies to improve patient outcomes. The purpose of this study was to investigate the function and regulatory mechanism of m6A modifications in CCA cell stemness.

Methods

Interleukin 6 (IL-6) treatment was used to induce an inflammatory response, and loss-of-function studies were conducted using mammosphere culture assays. Chromatin immunoprecipitation, polysome profiling, and methylated RNA immunoprecipitation analyses were used to identify signaling pathways. The in vitro findings were verified in a mice model.

Results

We first identified that m6A writers were highly expressed in CCAs and further showed that STAT3 directly bound to the gene loci of m6A writers, showing that IL-6/STAT3 signaling regulated expressions of m6A writers. Downregulating m6A writers prevented cell proliferation and migration in vitro and suppressed CCA tumorigenesis in vivo. Notably, the knockdown of m6A writers inhibited CCA cell stemness that was triggered by IL-6 treatment. Mechanistically, IGF2BP2 was bound to CTNNB1 transcripts, significantly enhancing their stability and translation, and conferring stem-like properties. Finally, we confirmed that the combination of m6A writers, IGF2BP2, and CTNNB1 distinguished CCA tissues from normal tissues.

Conclusions

Overall, this study showed that the IL-6-triggered inflammatory response facilitated the expressions of m6A writers and cell stemness in an m6A-IGF2BP2-dependent manner. Furthermore, the study showed that m6A modification was a targetable mediator of the response to inflammation factor exposure, was a potential diagnostic biomarker for CCA, and was critical to the progression of CCA.

Keywords

CholangiocarcinomaIL-6IGF2BP2cell stemnessN6-methyladenosine (m6A)

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References

1

Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013; 145: 1215-29.
Crossref Google Scholar
2

Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma – evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018; 15: 95-111.
Crossref Google Scholar
3

Tao LY, He XD, Qu Q, Cai L, Liu W, Zhou L, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a case-control study in China. Liver Int. 2010; 30: 215-21.
Crossref Google Scholar
4

Xun XD, Li Q. Surgical treatment of intrahepatic cholangiocarcinoma: a retrospective study of 104 cases. Cancer Biol Med. 2016; 13: 469-73.
Crossref Google Scholar
5

Pol S, Vallet-Pichard A, Hermine O. Extrahepatic cancers and chronic HCV infection. Nat Rev Gastroenterol Hepatol. 2018; 15: 283-90.
Crossref Google Scholar
6

Yan C, Koda S, Wu J, Zhang BB, Yu Q, Netea MG, et al. Roles of trained immunity in the pathogenesis of cholangiopathies: a novel therapeutic target. Hepatology. 2020; 72: 1838-50.
Crossref Google Scholar
7

Wang WT, Ye H, Wei PP, Han BW, He B, Chen ZH, et al. LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner. J Hematol Oncol. 2016; 9: 117.
Crossref Google Scholar
8

Lin KY, Ye H, Han BW, Wang WT, Wei PP, He B, et al. Genome-wide screen identified let-7c/miR-99a/miR-125b regulating tumor progression and stem-like properties in cholangiocarcinoma. Oncogene. 2016; 35: 3376-86.
Crossref Google Scholar
9

Wang WT, Han C, Sun YM, Chen TQ, Chen YQ. Noncoding RNAs in cancer therapy resistance and targeted drug development. J Hematol Oncol. 2019; 12: 55.
Crossref Google Scholar
10

Garner H, de Visser KE. Immune crosstalk in cancer progression and metastatic spread: a complex conversation. Nat Rev Immunol. 2020; 20: 483-97.
Crossref Google Scholar
11

Fu Y, Dominissini D, Rechavi G, He C. Gene expression regulation mediated through reversible m(6)A RNA methylation. Nat Rev Genet. 2014; 15: 293-306.
Crossref Google Scholar
12

Shi H, Wei J, He C. Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell. 2019; 74: 640-50.
Crossref Google Scholar
13

Liu J, Harada BT, He C. Regulation of gene expression by N(6)-methyladenosine in cancer. Trends Cell Biol. 2019; 29: 487-99.
Crossref Google Scholar
14

Chen ZH, Chen TQ, Zeng ZC, Wang D, Han C, Sun YM, et al. Nuclear export of chimeric mRNAs depends on an lncRNA-triggered autoregulatory loop in blood malignancies. Cell Death Dis. 2020; 11: 566.
Crossref Google Scholar
15

Pan Y, Ma P, Liu Y, Li W, Shu Y. Multiple functions of m(6)A RNA methylation in cancer. J Hematol Oncol. 2018; 11: 48.
Crossref Google Scholar
16

Pinello N, Sun S, Wong JJ. Aberrant expression of enzymes regulating m(6)A mRNA methylation: implication in cancer. Cancer Biol Med. 2018; 15: 323-34.
Crossref Google Scholar
17

Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, et al. The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 2017; 23: 1369-76.
Crossref Google Scholar
18

Ma JZ, Yang F, Zhou CC, Liu F, Yuan JH, Wang F, et al. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N(6)-methyladenosine-dependent primary MicroRNA processing. Hepatology. 2017; 65: 529-43.
Crossref Google Scholar
19

Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, et al. Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science. 2015; 347: 1002-6.
Crossref Google Scholar
20

Visvanathan A, Patil V, Arora A, Hegde AS, Arivazhagan A, Santosh V, et al. Essential role of METTL3-mediated m(6)A modification in glioma stem-like cells maintenance and radioresistance. Oncogene. 2018; 37: 522-33.
Crossref Google Scholar
21

Li T, Hu PS, Zuo Z, Lin JF, Li X, Wu QN, et al. METTL3 facilitates tumor progression via an m(6)A-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol Cancer. 2019; 18: 112.
Crossref Google Scholar
22

Wang WT, Han C, Sun YM, Chen ZH, Fang K, Huang W, et al. Activation of the lysosome-associated membrane protein LAMP5 by DOT1L serves as a bodyguard for MLL fusion oncoproteins to evade degradation in leukemia. Clin Cancer Res. 2019; 25: 2795-808.
Crossref Google Scholar
23

Hu Y, Rao SS, Wang ZX, Cao J, Tan YJ, Luo J, et al. Exosomes from human umbilical cord blood accelerate cutaneous wound healing through miR-21-3p-mediated promotion of angiogenesis and fibroblast function. Theranostics. 2018; 8: 169-84.
Crossref Google Scholar
24

Martinotti S, Ranzato E. Scratch wound healing assay. Methods Mol Biol. 2020; 2109: 225-9.
Crossref Google Scholar
25

Sun YM, Wang WT, Zeng ZC, Chen TQ, Han C, Pan Q, et al. circMYBL2, a circRNA from MYBL2, regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression. Blood. 2019; 134: 1533-46.
Crossref Google Scholar
26

Won J, Cho Y, Lee D, Jeon BY, Ju JW, Chung S, et al. Clonorchis sinensis excretory-secretory products increase malignant characteristics of cholangiocarcinoma cells in three-dimensional co-culture with biliary ductal plates. PLoS Pathog. 2019; 15: e1007818.
Crossref Google Scholar
27

Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012; 489: 57-74.
Crossref Google Scholar
28

Mott JL, Gores GJ. Targeting IL-6 in cholangiocarcinoma therapy. Am J Gastroenterol. 2007; 102: 2171-2.
Crossref Google Scholar
29

Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. 2018; 18: 773-89.
Crossref Google Scholar
30

Yang Y, Hsu PJ, Chen YS, Yang YG. Dynamic transcriptomic m(6) A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018; 28: 616-24.
Crossref Google Scholar
31

Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018; 20: 285-95.
Crossref Google Scholar
32

Liao S, Sun H, Xu C. YTH domain: a family of N(6)-methyladenosine (m(6)A) readers. Genomics Proteomics Bioinformatics. 2018; 16: 99-107.
Crossref Google Scholar
33

Zhuo W, Liu Y, Li S, Guo D, Sun Q, Jin J, et al. Long noncoding RNA GMAN, up-regulated in gastric cancer tissues, is associated with metastasis in patients and promotes translation of ephrin A1 by competitively binding GMAN-AS. Gastroenterology. 2019; 156: 676-91.
Crossref Google Scholar
34

Baudin-Baillieu A, Hatin I, Legendre R, Namy O. Translation analysis at the genome scale by ribosome profiling. Methods Mol Biol. 2016; 1361: 105-24.
Crossref Google Scholar
35

Huang L, Cai J, Guo H, Gu J, Tong Y, Qiu B, et al. ID3 promotes stem cell features and predicts chemotherapeutic response of intrahepatic cholangiocarcinoma. Hepatology. 2019; 69: 1995-2012.
Crossref Google Scholar
36

Wu HJ, Chu PY. Role of Cancer stem cells in cholangiocarcinoma and therapeutic implications. Int J Mol Sci. 2019; 20: 4154.
Crossref Google Scholar
37

Raggi C, Correnti M, Sica A, Andersen JB, Cardinale V, Alvaro D, et al. Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages. J Hepatol. 2017; 66: 102-15.
Crossref Google Scholar
38

Wang WT, Chen TQ, Zeng ZC, Pan Q, Huang W, Han C, et al. The lncRNA LAMP5-AS1 drives leukemia cell stemness by directly modulating DOT1L methyltransferase activity in MLL leukemia. J Hematol Oncol. 2020; 13: 78.
Crossref Google Scholar
39

Carpino G, Cardinale V, Folseraas T, Overi D, Grzyb K, Costantini D, et al. Neoplastic transformation of the peribiliary stem cell niche in cholangiocarcinoma arisen in primary sclerosing cholangitis. Hepatology. 2019; 69: 622-38.
Crossref Google Scholar
40

Bharti R, Dey G, Mandal M. Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: a snapshot of IL-6 mediated involvement. Cancer Lett. 2016; 375: 51-61.
Crossref Google Scholar
41

Carotenuto P, Fassan M, Pandolfo R, Lampis A, Vicentini C, Cascione L, et al. Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers. Gut. 2017; 66: 1268-77.
Crossref Google Scholar
42

Hou J, Zhang H, Liu J, Zhao Z, Wang J, Lu Z, et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma. Mol Cancer. 2019; 18: 163.
Crossref Google Scholar
43

Feng Z, Li Q, Meng R, Yi B, Xu Q. METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide-induced inflammatory response in human dental pulp cells. J Cell Mol Med. 2018; 22: 2558-68.
Crossref Google Scholar
44

Jin D, Guo J, Wu Y, Du J, Yang L, Wang X, et al. m(6)A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis. J Hematol Oncol. 2019; 12: 135.
Crossref Google Scholar
45

Wang Y, Li Y, Toth JI, Petroski MD, Zhang Z, Zhao JC. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nature Cell Biology. 2014; 16: 191-8.
Crossref Google Scholar
46

Zhang C, Huang S, Zhuang H, Ruan S, Zhou Z, Huang K, et al. YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation. Oncogene. 2020; 39: 4507-18.
Crossref Google Scholar
Cancer Biology & Medicine
Volume 19 Issue 3,
March 2022
Pages 343-357
DOI: 10.20892/j.issn.2095-3941.2020.0661
Cite this article:
Ye H, Chen T, Zeng Z, et al. The m6A writers regulated by the IL-6/STAT3 inflammatory pathway facilitate cancer cell stemness in cholangiocarcinoma. Cancer Biology & Medicine, 2022, 19(3): 343-357. https://doi.org/10.20892/j.issn.2095-3941.2020.0661

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Received: 22 October 2020
Accepted: 05 March 2021
Published: 15 March 2022
©2022 Cancer Biology & Medicine.

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