MOR/ERK signalling pathway promotes the malignant progression of residual hepatocellular carcinoma cells after insufficient radiofrequency ablation

Qianxi Yin; Fengjuan Li; Feiyan Gao; Xiaoying He; Ying Liu; Yang Liu; Jiwei Liu; Shujun Liu; Guoqun Jia; Libing Ma

doi:10.22317/jcms.v11i2.1691

Authors

Qianxi Yin College of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China.
Fengjuan Li Baotou Central Hospital, Baotou, Inner Mongolia 014040, China.
Feiyan Gao College of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China.
Xiaoying He College of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China; Inner Mongolia Key Laboratory of Life Health and Bioinformatics, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China.
Ying Liu College of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China; Inner Mongolia Key Laboratory of Life Health and Bioinformatics, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China.
Yang Liu College of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China; Inner Mongolia Key Laboratory of Life Health and Bioinformatics, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China.
Jiwei Liu College of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China; Inner Mongolia Key Laboratory of Life Health and Bioinformatics, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China.
Shujun Liu College of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China; Inner Mongolia Key Laboratory of Life Health and Bioinformatics, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China.
Guoqun Jia The First Hospital Affiliated to Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China.
Libing Ma College of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China; Inner Mongolia Key Laboratory of Life Health and Bioinformatics, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, China.

DOI:

https://doi.org/10.22317/jcms.v11i2.1691

Keywords:

μ-opioid receptor, hepatocellular carcinoma, radiofrequency ablation, ERK

Abstract

Objective: Radiofrequency ablation (RFA) is the first-line of treatment for unresectable early hepatocellular carcinoma (HCC). However, the accelerated malignancy progression of residual HCC cells post-RFA pose a major obstacle to its clinical application. The mechanisms underlying the increased malignancy of residual HCC cells following RFA require further investigation.

Methods: In the present study, HepG2 cells, an established human HCC cell line, were subjected to repeated heat treatment to simulate residual HCC cells after RFA, surviving cells were designated as HepG2-H cells. Malignancy parameters and μ-opioid receptor (MOR) expression levels were compared between HepG2 and HepG2-H cells. RNA sequencing was subsequently performed to identify differentially expressed genes (DEGs) between the two groups of cells, and pathways enrichment analysis was conducted to investigate signaling pathways potentially driving HepG2-H cells malignancy.

Results: HepG2-H cells exhibited significantly elevated malignancy compared to HepG2 cells, as evidenced by enhanced proliferation, migration, and colony formation. MOR expression was significantly upregulated in HepG2-H cells. RNA sequencing revealed that DEGs between the two groups were predominantly enriched in cancer pathways. Furthermore, phosphorylated ERK1/2 (P-ERK1/2) levels were 1.18-fold higher in HepG2-H cells, and the inhibition of MOR activity could reduce both the level of P-ERK1/2 and the malignancy of HepG2-H cells.

Conclusion: Our findings suggest that the activation of MOR/ERK signaling pathway contributes to the malignant progression of residual HCC cells post-RFA. Targeting MOR may offer a novel therapeutic strategy to mitigate tumor recurrence following RFA.

References

Konyn P, Ahmed A, Kim D. Current epidemiology in hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol. 2021, 15: 1295-1307.

Strand NH, Hagedorn JM, Dunn T, Johnson B, Abd-Elsayed A, Covington S, et al. Advances in radiofrequency ablation: mechanism of action and technology. Ann Palliat Med. 2024, 13: 1028-1034.

Chen L, Sun J, Yang X. Radiofrequency ablation-combined multimodel therapies for hepatocellular carcinoma: Current status. Cancer Lett. 2016, 370: 78-84.

Wu X, Lokken RP, Mehta N. Optimal treatment for small HCC (<3 cm): Resection, liver transplantation, or locoregional therapy? JHEP Rep. 2023, 5: 100781.

Salmi A, Turrini R, Lanzani G, Viviani G, Zappella A, Savio A, et al. Long-term effectiveness of radiofrequency ablation for hepatocellular carcinoma of 3.5 cm or less. Hepatogastroenterology. 2008, 55: 191-196.

Zhao Z, Wu J, Liu X, Liang M, Zhou X, Ouyang S, et al. Insufficient radiofrequency ablation promotes proliferation of residual hepatocellular carcinoma via autophagy. Cancer Lett. 2018, 421: 73-81.

Zhang N, Ma D, Wang L, Zhu X, Pan Q, Zhao Y, et al. Insufficient Radiofrequency Ablation Treated Hepatocellular Carcinoma Cells Promote Metastasis by Up-Regulation ITGB3. J Cancer. 2017, 8: 3742-3754.

Feng Y, He X, Yang Y, Chao D, Lazarus LH, Xia Y. Current research on opioid receptor function. Curr Drug Targets. 2012, 13: 230-246.

Lennon FE, Mirzapoiazova T, Mambetsariev B, Poroyko VA, Salgia R, Moss J, et al. The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and Epithelial Mesenchymal Transition (EMT) in human lung cancer. PLoS One. 2014, 9: e91577.

Lu H, Zhang H, Weng ML, Zhang J, Jiang N, Cata JP, et al. Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer. J Cell Physiol. 2021, 236: 4445-4454.

Li Y, Li G, Tao T, Kang X, Liu C, Zhang X, et al. The μ-opioid receptor (MOR) promotes tumor initiation in hepatocellular carcinoma. Cancer Lett. 2019, 453: 1-9.

Zhang H, Zhou D, Gu J, Qu M, Guo K, Chen W, et al. Targeting the mu-Opioid Receptor for Cancer Treatment. Curr Oncol Rep. 2021, 23: 111.

Ramirez MF, Gorur A, Cata JP. Opioids and cancer prognosis: A summary of the clinical evidence. Neurosci Lett. 2021, 746: 135661.

Kong J, Pan B, Ke S, Dong S, Li X, Zhou A, et al. Insufficient radiofrequency ablation promotes angiogenesis of residual hepatocellular carcinoma via HIF-1α/VEGFA. PLoS One. 2012, 7: e37266.

Zhang N, Li H, Qin C, Ma D, Zhao Y, Zhu W, et al. Insufficient radiofrequency ablation promotes the metastasis of residual hepatocellular carcinoma cells via upregulating flotillin proteins. J Cancer Res Clin Oncol. 2019, 145: 895-907.

Tan Y, Zhao L. miR-103 promotes hepatocellular carcinoma cell proliferation and migration in the simulation transition zone of RFA through PI3K/Akt signaling pathway by targeting PTEN. Int J Clin Exp Pathol. 2020, 13: 473-479.

Li G, Kong J, Dong S, Niu H, Wu S, Sun W. Circular BANP knockdown inhibits the malignant progression of residual hepatocellular carcinoma after insufficient radiofrequency ablation. Chin Med J (Engl). 2022, 135: 1578-1587.

Zhou HQ, Liu MS, Deng TB, Xie PB, Wang W, Shao T, et al. The TGF-β/Smad Pathway Inhibitor SB431542 Enhances The Antitumor Effect Of Radiofrequency Ablation On Bladder Cancer Cells. Onco Targets Ther. 2019, 12: 7809-7821.

Song Y, Bi Z, Liu Y, Qin F, Wei Y, Wei X. Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer: Current status in clinical trials. Genes Dis. 2022, 10: 76-88.

Li L, Zhao GD, Shi Z, Qi LL, Zhou LY, Fu ZX. The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncol Lett. 2016, 12: 3045-3050.

Deng Q, He M, Fu C, Feng K, Ma K, Zhang L. Radiofrequency ablation in the treatment of hepatocellular carcinoma. Int J Hyperthermia. 2022, 39: 1052-1063.

Guo Y, Ren Y, Dong X, Kan X, Zheng C. An Overview of Hepatocellular Carcinoma After Insufficient Radiofrequency Ablation. J Hepatocell Carcinoma. 2022, 9: 343-355.

Jia G, Li F, Tong R, Liu Y, Zuo M, Ma L, et al. c-Met/MAPK pathway promotes the malignant progression of residual hepatocellular carcinoma cells after insufficient radiofrequency ablation. Med Oncol. 2020, 37: 117.

Su T, Huang M, Liao J, Lin S, Yu P, Yang J, et al. Insufficient Radiofrequency Ablation Promotes Hepatocellular Carcinoma Metastasis Through N6-Methyladenosine mRNA Methylation-Dependent Mechanism. Hepatology. 2021, 74: 1339-1356.

Ikemoto T, Shimada M, Yamada S. Pathophysiology of recurrent hepatocellular carcinoma after radiofrequency ablation. Hepatol Res. 2017, 47: 23-30.

Xiong B, Li C, Hong G, Li J, Luo Q, Gong J, et al. HMGB1/TREM1 crosstalk between heat-injured hepatocytes and macrophages promotes HCC progression after RFA. J Cancer Res Clin Oncol. 2024, 150: 480.

Ramirez MF, Gorur A, Cata JP. Opioids and cancer prognosis: A summary of the clinical evidence. Neurosci Lett. 2021, 746: 135661.

Novy DM, Nelson DV, Koyyalagunta D, Cata JP, Gupta P, Gupta K. Pain, opioid therapy, and survival: a needed discussion. Pain. 2020, 161: 496-501.

Lennon FE, Mirzapoiazova T, Mambetsariev B, Salgia R, Moss J, Singleton PA. Overexpression of the μ-opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis. Anesthesiology. 2012, 116: 857-867.

Zhang M, Su J, Zhang Y, Xu J, Zhang S. Conveying endogenous and exogenous signals: MAPK cascades in plant growth and defense. Curr Opin Plant Biol. 2018, 45(Pt A): 1-10.

Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002, 12: 9-18.

Chen C, Nelson LJ, Ávila MA, Cubero FJ. Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link. Cells. 2019, 8: 1172.

Timofeev O, Giron P, Lawo S, Pichler M, Noeparast M. ERK pathway agonism for cancer therapy: evidence, insights, and a target discovery framework. NPJ Precis Oncol. 2024, 8: 70.

Pan X, Pei J, Wang A, Shuai W, Feng L, Bu F, et al. Development of small molecule extracellular signal-regulated kinases (ERKs) inhibitors for cancer therapy. Acta Pharm Sin B. 2022, 12: 2171-2192.

MOR/ERK signalling pathway promotes the malignant progression of residual hepatocellular carcinoma cells after insufficient radiofrequency ablation

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