Unraveling Chemoresistance Mechanisms in Hepatocellular Carcinoma

• Sidra Javed

  School of Biological Sciences, University of the Punjab, Q-A Campus, Lahore, 54590, Pakistan

  Author

  https://orcid.org/0009-0009-9014-8992

• Isbah Ashfaq

  Institute of Zoology, University of the Punjab, Q-A Campus, Lahore, 54590, Pakistan

  Author

  https://orcid.org/0000-0002-2485-7143

• Mehak Shahid

  School of Biological Sciences, University of the Punjab, Q-A Campus, Lahore, 54590, Pakistan

  Author

  https://orcid.org/0000-0002-0248-1886

• Asima Tayyeb

  School of Biological Sciences, University of the Punjab, Q-A Campus, Lahore, 54590, Pakistan

  Author

  https://orcid.org/0000-0003-0629-3740

Hepatocellular carcinoma (HCC) is an aggressive tumor among liver malignancies, and a predominant cause of cancer related mortalities around the globe. HCC heterogeneity at both the molecular and phenotypic levels complicate disease diagnosis, prognosis, and treatment responses.  Despite advancements in standard therapeutic approaches, ranging from surgical resection to systemic therapies, the disease prognosis remains poor in advanced stages. Several available chemotherapies and multikinase inhibitors have been effectively used to target oncogenic pathways. However, the development of chemoresistance continues to limit the effectiveness of inhibitors, as drug resistance involves an interplay of complex mechanisms, including altered drug transport, dysregulation of intracellular signaling, genetic modifications, and epigenetic reprogramming. Furthermore, chronic inflammation within the tumor microenvironment promotes tumor metastasis and reduced drug sensitivity by activating pro-tumorigenic signaling cascades, such as dysregulation of the JAK/STAT pathway mediated by altered expression of suppressors of cytokines. Additionally, epithelial-to-mesenchymal transitions, cancer stemness, autophagy, and immune evasion are factors that reinforce both innate and acquired resistance. Immune checkpoint inhibitors among immunotherapies proposed new hope for treatment of HCC, but interacting resistance mechanisms have made their effectiveness inconsistence. This review summarizes the molecular mechanisms underlying chemoresistance and highlights how understanding these factors can aid the development of advance therapeutic strategies to enhance treatment outcomes.

Abdelhamed, W., & El-Kassas, M. (2024). Hepatitis B virus as a risk factor for hepatocellular carcinoma: There is still much work to do. Liver Research, 8(2), 83–90. https://doi.org/10.1016/j.livres.2024.05.004

AlAbdulla, R., Lozano, E., Macias, R. I. R., Monte, M. J., Briz, O., O’Rourke, C. J., Serrano, M. A., Banales, J. M., Avila, M. A., Martinez‐Chantar, M. L., Geier, A., Andersen, J. B., & Marin, J. J. G. (2018). Epigenetic events involved in organic cation transporter 1 dependent impaired response of hepatocellular carcinoma to sorafenib. British Journal of Pharmacology, 176(6), 787–800. https://doi.org/10.1111/bph.14563

Alemohammad, H., Motafakkerazad, R., Asadzadeh, Z., Farsad, N., Hemmat, N., Najafzadeh, B., Vasefifar, P., & Baradaran, B. (2022). siRNA-mediated silencing of Nanog reduces stemness properties and increases the sensitivity of HepG2 cells to cisplatin. Gene, 821, 146333. https://doi.org/10.1016/j.gene.2022.146333

Ahmad, H., Ashfaq, I., Tayyeb, A., Ameen, E., & Sheikh, N. (2025). Role of SOCS2 in Chemokine Signalling and its Impact on Hepatocellular Carcinoma Cells. Zeitschrift Für Gastroenterologie, 63(01), e7. https://doi.org/10.1055/s-0044-1801003

Arechederra, M., Bazai, S. K., Abdouni, A., Sequera, C., Mead, T. J., Richelme, S., Daian, F., Audebert, S., Dono, R., Lozano, A., Gregoire, D., Hibner, U., Allende, D. S., Apte, S. S., & Maina, F. (2020). ADAMTSL5 is an epigenetically activated gene underlying tumorigenesis and drug resistance in hepatocellular carcinoma. Journal of Hepatology, 74(4), 893–906. https://doi.org/10.1016/j.jhep.2020.11.008

Ashfaq, I., Sheikh, N., Fatima, N., & Tayyeb, A. (2022). Inhibition of anti-inflammatory pathway through suppressors of cytokine signalling (Socs2/Socs3) in the initiation of hepatocellular carcinoma. Saudi Journal of Biological Sciences, 29(8), 103348. https://doi.org/10.1016/j.sjbs.2022.103348

Bellentani, S. (2020). Epidemiology of hepatocellular carcinoma in metabolic liver disease. Hepatoma Research, 2020. https://doi.org/10.20517/2394-5079.2020.10

Blandino, G., & Di Agostino, S. (2018). New therapeutic strategies to treat human cancers expressing mutant p53 proteins. Journal of Experimental & Clinical Cancer Research, 37(1). https://doi.org/10.1186/s13046-018-0705-7

Chen, K., Tai, W., Liu, T., Huang, H., Lin, Y., Shiau, C., Li, P., Chen, P., & Cheng, A. (2010). Sorafenib Overcomes TRAIL Resistance of Hepatocellular Carcinoma Cells through the Inhibition of STAT3. Clinical Cancer Research, 16(21), 5189–5199. https://doi.org/10.1158/1078-0432.ccr-09-3389

Chen, M., Neul, C., Schaeffeler, E., Frisch, F., Winter, S., Schwab, M., Koepsell, H., Hu, S., Laufer, S., Baker, S. D., Sparreboom, A., & Nies, A. T. (2019). Sorafenib Activity and Disposition in Liver Cancer Does Not Depend on Organic Cation Transporter 1. Clinical Pharmacology & Therapeutics, 107(1), 227–237. https://doi.org/10.1002/cpt.1588

Chen, K., Tai, W., Liu, T., Huang, H., Lin, Y., Shiau, C., Li, P., Chen, P., & Cheng, A. (2010). Sorafenib Overcomes TRAIL Resistance of Hepatocellular Carcinoma Cells through the Inhibition of STAT3. Clinical Cancer Research, 16(21), 5189–5199. https://doi.org/10.1158/1078-0432.ccr-09-3389

Cheng, L., Zhang, L., Wang, X., Wang, Y., Yu, J., Li, M., Ma, Z., Ho, P. C., Chen, X., Wang, L., Sethi, G., & Goh, B. (2024). Extracellular Vesicles in the HCC Microenvironment: Implications for Therapy and Biomarkers. Pharmacological Research, 107419. https://doi.org/10.1016/j.phrs.2024.107419

Choi, N. R., Kim, J. Y., Hong, J. H., Hur, M. H., Cho, H., Park, M. K., Kim, J., Lee, Y. B., Cho, E. J., Lee, J., Yu, S. J., Yoon, J., & Kim, Y. J. (2022). Comparison of the outcomes between sorafenib and lenvatinib as the first-line systemic treatment for HBV-associated hepatocellular carcinoma: a propensity score matching analysis. BMC Gastroenterology, 22(1). https://doi.org/10.1186/s12876-022-02210-3

Daud, A. I., Wolchok, J. D., Robert, C., Hwu, W., Weber, J. S., Ribas, A., Hodi, F. S., Joshua, A. M., Kefford, R., Hersey, P., Joseph, R., Gangadhar, T. C., Dronca, R., Patnaik, A., Zarour, H., Roach, C., Toland, G., Lunceford, J. K., Li, X. N., . . . Hamid, O. (2016). Programmed Death-Ligand 1 Expression and Response to the Anti–Programmed Death 1 Antibody Pembrolizumab in Melanoma. Journal of Clinical Oncology, 34(34), 4102–4109. https://doi.org/10.1200/jco.2016.67.2477

Dhamija, E., Paul, S. B., & Kedia, S. (2019). Non-alcoholic fatty liver disease associated with hepatocellular carcinoma: An increasing concern. The Indian Journal of Medical Research, 149(1), 9. https://doi.org/10.4103/ijmr.ijmr_1456_17

Dong, C., Zhao, B., Long, F., Liu, Y., Liu, Z., Li, S., Yang, X., Sun, D., Wang, H., Liu, Q., Liang, R., Li, Y., Gao, Z., Shao, S., Miao, Q. R., & Wang, L. (2016). Nogo-B receptor promotes the chemoresistance of human hepatocellular carcinoma via the ubiquitination of p53 protein. Oncotarget, 7(8), 8850–8865. https://doi.org/10.18632/oncotarget.7091

El-Khoueiry, A. B., O’Donnell, R., Semrad, T. J., Mack, P., Blanchard, S., Bahary, N., Jiang, Y., Yen, Y., Wright, J., Chen, H., Lenz, H., & Gandara, D. R. (2018b). A phase I trial of escalating doses of cixutumumab (IMC-A12) and sorafenib in the treatment of advanced hepatocellular carcinoma. Cancer Chemotherapy and Pharmacology, 81(5), 957–963. https://doi.org/10.1007/s00280-018-3553-4

Fan, L., Huang, X., Chen, J., Zhang, K., Gu, Y., Sun, J., & Cui, S. (2020). Long Noncoding RNA MALAT1 Contributes to Sorafenib Resistance by Targeting miR-140-5p/Aurora-A Signaling in Hepatocellular Carcinoma. Molecular Cancer Therapeutics, 19(5), 1197–1209. https://fdoi.org/10.1158/1535-7163.mct-19-0203

Fang, Y., Xue, J., Shen, Q., Chen, J., & Tian, L. (2012). MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. Hepatology, 55(6), 1852–1862. https://doi.org/10.1002/hep.25576

Ferlay, J., Colombet, M., Soerjomataram, I., Mathers, C., Parkin, D., Piñeros, M., Znaor, A., & Bray, F. (2018). Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International Journal of Cancer, 144(8), 1941–1953. https://doi.org/10.1002/ijc.31937

Fornari, F., Pollutri, D., Patrizi, C., La Bella, T., Marinelli, S., Gardini, A. C., Marisi, G., Toaldo, M. B., Baglioni, M., Salvatore, V., Callegari, E., Baldassarre, M., Galassi, M., Giovannini, C., Cescon, M., Ravaioli, M., Negrini, M., Bolondi, L., & Gramantieri, L. (2017). In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3–Mediated Apoptosis. Clinical Cancer Research, 23(14), 3953–3965. https://doi.org/10.1158/1078-0432.ccr-16-1464

Fouquet, G., Debuysscher, V., Ouled-Haddou, H., Eugenio, M. S., Demey, B., Singh, A. R., Ossart, C., Bagami, M. A., Regimbeau, J., Nguyen-Khac, E., Naassila, M., Marcq, I., & Bouhlal, H. (2016). Hepatocyte SLAMF3 reduced specifically the multidrugs resistance protein MRP-1 and increases HCC cells sensitization to anti-cancer drugs. Oncotarget, 7(22), 32493–32503. https://doi.org/10.18632/oncotarget.8679

Gao, R., Kalathur, R. K. R., Coto‐Llerena, M., Ercan, C., Buechel, D., Shuang, S., Piscuoglio, S., Dill, M. T., Camargo, F. D., Christofori, G., & Tang, F. (2021). YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO Molecular Medicine, 13(12). https://doi.org/10.15252/emmm.202114351

Gao, J., Dai, C., Yu, X., Yin, X., & Zhou, F. (2020). Long noncoding RNA LEF1‐AS1 acts as a microRNA‐10a‐5p regulator to enhance MSI1 expression and promote chemoresistance in hepatocellular carcinoma cells through activating AKT signaling pathway. Journal of Cellular Biochemistry, 122(1), 86–99. https://doi.org/10.1002/jcb.29833

Gao, J., Rong, Y., Huang, Y., Shi, P., Wang, X., Meng, X., Dong, J., & Wu, C. (2018). Cirrhotic stiffness affects the migration of hepatocellular carcinoma cells and induces sorafenib resistance through YAP. Journal of Cellular Physiology, 234(3), 2639–2648. https://doi.org/10.1002/jcp.27078

García-Aranda, M., Pérez-Ruiz, E., & Redondo, M. (2018). Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy. International Journal of Molecular Sciences, 19(12), 3950. https://doi.org/10.3390/ijms19123950

Guo, X. G., Wang, Z. H., Dong, W., He, X. D., Liu, F. C., & Liu, H. (2018). Specific CYP450 Genotypes in the Chinese Population Affect Sorafenib Toxicity in HBV/HCV-associated Hepatocellular Carcinoma Patients. PubMed, 31(8), 586–595. https://doi.org/10.3967/bes2018.080Huang, W., Hsieh, Y., Hung, C., Chien, P., Chien, Y., Chen, L., Tu, C., Chen, C., Hsu, S., Lin, Y., & Chen, Y. (2013). BCRP/ABCG2 inhibition sensitizes hepatocellular carcinoma cells to sorafenib. PLoS ONE, 8(12), e83627. https://doi.org/10.1371/journal.pone.0083627

Jiang, X., Yu, X., Liu, T., Zhu, H., Shi, X., Bilegsaikhan, E., Guo, H., Song, G., Weng, S., Huang, X., Dong, L., Janssen, H. L., Shen, X., & Zhu, J. (2018). microRNA-19a-3p promotes tumor metastasis and chemoresistance through the PTEN/Akt pathway in hepatocellular carcinoma. Biomedicine & Pharmacotherapy, 105, 1147–1154. https://doi.org/10.1016/j.biopha.2018.06.097

Jiang, L., Chan, J. Y., & Fung, K. (2012). Epigenetic loss of CDH1 correlates with multidrug resistance in human hepatocellular carcinoma cells. Biochemical and Biophysical Research Communications, 422(4), 739–744. https://doi.org/10.1016/j.bbrc.2012.05.072

Ladd, A. D., Duarte, S., Sahin, I., & Zarrinpar, A. (2023). Mechanisms of drug resistance in HCC. Hepatology. https://doi.org/10.1097/hep.0000000000000237

Lai, S., Su, Y., Chi, C., Kuo, Y., Lee, K., Wu, Y., Lan, P., Yang, M., Chang, T., & Huang, Y. (2019). DNMT3b/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6/STAT3 regulation. Journal of Experimental & Clinical Cancer Research, 38(1). https://doi.org/10.1186/s13046-019-1442-2

Kim, S. Y., Kim, D., Kim, J., Ko, H. Y., Kim, W. J., Park, Y., Lee, H. W., Han, D. H., Kim, K. S., Park, S., Lee, M., & Yun, M. (2022). Extracellular Citrate Treatment Induces HIF1α Degradation and Inhibits the Growth of Low-Glycolytic Hepatocellular Carcinoma under Hypoxia. Cancers, 14(14), 3355. https://doi.org/10.3390/cancers14143355

Koshy, A. (2024). Evolving global etiology of hepatocellular carcinoma (HCC): Insights and trends for 2024. Journal of Clinical and Experimental Hepatology, 15(1), 102406. https://doi.org/10.1016/j.jceh.2024.102406

Lei, Y., He, X., Li, J., & Mo, C. (2024). Drug Resistance in Hepatocellular Carcinoma: Theoretical Basis and Therapeutic Aspects. Frontiers in Bioscience-Landmark, 29(2), 52. https://doi.org/10.31083/j.fbl2902052

Li, Q., Zhang, Y., Jin, P., Chen, Y., Zhang, C., Geng, X., Mun, K. S., & Phang, K. C. (2024). New insights into the potential of exosomal circular RNAs in mediating cancer chemotherapy resistance and their clinical applications. Biomedicine & Pharmacotherapy, 177, 117027. https://doi.org/10.1016/j.biopha.2024.117027

Li, Q., Wang, C., Wang, Y., Sun, L., Liu, Z., Wang, L., Song, T., Yao, Y., Liu, Q., & Tu, K. (2018). HSCs-derived COMP drives hepatocellular carcinoma progression by activating MEK/ERK and PI3K/AKT signaling pathways. Journal of Experimental & Clinical Cancer Research, 37(1). https://doi.org/10.1186/s13046-018-0908-y

Li, X., Yang, X., Biskup, E., Zhou, J., Li, H., Wu, Y., Chen, M., & Xu, F. (2015). Co-expression of CXCL8 and HIF-1α is associated with metastasis and poor prognosis in hepatocellular carcinoma. Oncotarget, 6(26), 22880–22889. https://doi.org/10.18632/oncotarget.4412

Liang, Y., Chen, J., Yu, Q., Ji, T., Zhang, B., Xu, J., Dai, Y., Xie, Y., Lin, H., Liang, X., & Cai, X. (2017). Phosphorylated ERK is a potential prognostic biomarker for Sorafenib response in hepatocellular carcinoma. Cancer Medicine, 6(12), 2787–2795. https://doi.org/10.1002/cam4.1228

Liang, Y., Liang, Q., Qiao, L., & Xiao, F. (2020). MicroRNAs Modulate Drug Resistance-Related Mechanisms in Hepatocellular Carcinoma. Frontiers in Oncology, 10. https://doi.org/10.3389/fonc.2020.00920

Liu, C., Wu, H., Mao, Y., Chen, W., & Chen, S. (2021). Exosomal microRNAs in hepatocellular carcinoma. Cancer Cell International, 21(1). https://doi.org/10.1186/s12935-021-01941-9

Liao, L. Z., Chen, C. T., Li, N. C., Lin, L. C., Huang, B. S., Chang, Y. H., & Chow, L. P. (2020). Y-box binding protein-1 promotes epithelial-mesenchymal transition in sorafenib-resistant hepatocellular carcinoma cells. International journal of molecular sciences, 22(1), 224. https://doi.org/10.3390/ijms22010224

Lv, S., Wang, X., Bai, X., Ning, H., Li, Y., Wen, H., Lu, W., & Wang, J. (2020). Mesenchymal epithelial transition factor regulates tumor necrosis factor-related apoptotic induction ligand resistance in hepatocellular carcinoma cells through down-regulation of cyclin B1. The International Journal of Biochemistry & Cell Biology, 128, 105844. https://doi.org/10.1016/j.biocel.2020.105844

Ma, Y., Xu, R., Liu, X., Zhang, Y., Song, L., Cai, S., Zhou, S., Xie, Y., Li, A., Cao, W., & Tang, X. (2021). LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells. International Journal of Medical Sciences, 18(6), 1456–1464. https://doi.org/10.7150/ijms.51256

Marin, J., Monte, M., Macias, R., Romero, M., Herraez, E., Asensio, M., Ortiz-Rivero, S., Cives-Losada, C., Di Giacomo, S., Gonzalez-Gallego, J., Mauriz, J., Efferth, T., & Briz, O. (2022). Expression of Chemoresistance-Associated ABC proteins in hepatobiliary, pancreatic and gastrointestinal cancers. Cancers, 14(14), 3524. https://doi.org/10.3390/cancers14143524

Marin, J. J., Macias, R. I., Monte, M. J., Romero, M. R., Asensio, M., Sanchez-Martin, A., Cives-Losada, C., Temprano, A. G., Espinosa-Escudero, R., Reviejo, M., Bohorquez, L. H., & Briz, O. (2020). Molecular Bases of Drug Resistance in Hepatocellular Carcinoma. Cancers, 12(6), 1663. https://doi.org/10.3390/cancers12061663

Marin, J. J., Monte, M. J., Blazquez, A. G., Macias, R. I., Serrano, M. A., & Briz, O. (2013). The role of reduced intracellular concentrations of active drugs in the lack of response to anticancer chemotherapy. Acta Pharmacologica Sinica, 35(1), 1–10. https://doi.org/10.1038/aps.2013.131Méndez-Blanco, C., Fondevila, F., García-Palomo, A., González-Gallego, J., & Mauriz, J. L. (2018). Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors. Experimental & Molecular Medicine, 50(10), 1–9. https://doi.org/10.1038/s12276-018-0159-1

Musa, S., Amara, N., Selawi, A., Wang, J., Marchini, C., Agbarya, A., & Mahajna, J. (2024). Overcoming Chemoresistance in Cancer: The Promise of Crizotinib. Cancers, 16(13), 2479. https://doi.org/10.3390/cancers16132479

Pang, L., Xu, L., Yuan, C., Li, X., Zhang, X., Wang, W., Guo, X., Ouyang, Y., Qiao, L., Wang, Z., & Liu, K. (2019). Activation of EGFR‐KLF4 positive feedback loop results in acquired resistance to sorafenib in hepatocellular carcinoma. Molecular Carcinogenesis, 58(11), 2118–2126. https://doi.org/10.1002/mc.23102

Panneerselvam, S., Wilson, C., Kumar, P., Abirami, D., Pamarthi, J., Reddy, M. S., & Varghese, J. (2023). Overview of hepatocellular carcinoma: from molecular aspects to future therapeutic options. Cell Adhesion & Migration, 17(1), 1–21. https://doi.org/10.1080/19336918.2023.2258539

Pavlíková, L., Šereš, M., Breier, A., & Sulová, Z. (2022). The Roles of microRNAs in Cancer Multidrug Resistance. Cancers, 14(4), 1090. https://doi.org/10.3390/cancers14041090

Qu, Z., Wu, J., Wu, J., Luo, D., Jiang, C., & Ding, Y. (2016). Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro. Journal of Experimental & Clinical Cancer Research, 35(1). https://doi.org/10.1186/s13046-016-0430-z

Qu, B., Liu, B., Du, Y., Chen, J., Cheng, Y., Xu, W., & Wang, X. (2014). Wnt/β-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma. Oncology Letters, 7(4), 1175–1178. https://doi.org/10.3892/ol.2014.1828

Rios, R. S., Zheng, K. I., & Zheng, M. (2021). Non-alcoholic steatohepatitis and risk of hepatocellular carcinoma. Chinese Medical Journal, 134(24), 2911–2921. https://doi.org/10.1097/cm9.0000000000001888

Singal, A. G., Kanwal, F., & Llovet, J. M. (2023). Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nature Reviews Clinical Oncology, 20(12), 864–884. https://doi.org/10.1038/s41571-023-00825-3

Scialpi, R., Arrè, V., Giannelli, G., & Dituri, F. (2023). Laminin-332 γ2 Monomeric Chain Promotes Adhesion and Migration of Hepatocellular Carcinoma Cells. Cancers, 15(2), 373. https://doi.org/10.3390/cancers15020373

Shibue, T., & Weinberg, R. A. (2017). EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nature Reviews Clinical Oncology, 14(10), 611–629. https://doi.org/10.1038/nrclinonc.2017.44

Sokolov, E., Eheim, A. L., Ahrens, W. A., Walling, T. L., Swet, J. H., McMillan, M. T., Simo, K. A., Thompson, K. J., Sindram, D., & McKillop, I. H. (2012). Lysophosphatidic acid receptor expression and function in human hepatocellular carcinoma. Journal of Surgical Research, 180(1), 104–113. https://doi.org/10.1016/j.jss.2012.10.054

Song, Y., Kim, S., Kim, K. M., Choi, E. K., Kim, J., & Seo, H. R. (2016). Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids. Scientific Reports, 6(1). https://doi.org/10.1038/srep36750

Sun, J., Zhou, C., Zhao, Y., Zhang, X., Chen, W., Zhou, Q., Hu, B., Gao, D., Raatz, L., Wang, Z., Nelson, P. J., Jiang, Y., Ren, N., Bruns, C. J., & Zhou, H. (2021). Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation. Redox Biology, 41, 101942. https://doi.org/10.1016/j.redox.2021.101942

Tan, Z., Chiu, M. S., Yang, X., Yue, M., Cheung, T. T., Zhou, D., Wang, Y., Chan, A. W., Yan, C. W., Kwan, K. Y., Wong, Y. C., Li, X., Zhou, J., To, K. F., Zhu, J., Lo, C. M., Cheng, A. S., Chan, S. L., Liu, L., . . . Chen, Z. (2022). Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients. Gut, 72(8), 1568–1580. https://doi.org/10.1136/gutjnl-2022-327133

Tan, W., Luo, X., Li, W., Zhong, J., Cao, J., Zhu, S., Chen, X., Zhou, R., Shang, C., & Chen, Y. (2018). TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma. EBioMedicine, 40, 446–456. https://doi.org/10.1016/j.ebiom.2018.12.047

Teufel, M., Seidel, H., Köchert, K., Meinhardt, G., Finn, R. S., Llovet, J. M., & Bruix, J. (2019). Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma. Gastroenterology, 156(6), 1731–1741. https://doi.org/10.1053/j.gastro.2019.01.261

Thillai, K., Srikandarajah, K., & Ross, P. (2017). Regorafenib as treatment for patients with advanced hepatocellular cancer. Future Oncology, 13(25), 2223–2232. https://doi.org/10.2217/fon-2017-0204

Tian, Q. (2012). Astragalus polysaccharides can regulate cytokine and P-glycoprotein expression in H22 tumor-bearing mice. World Journal of Gastroenterology, 18(47), 7079. https://doi.org/10.3748/wjg.v18.i47.7079

Toh, M. R., Wong, E. Y. T., Wong, S. H., Ng, A. W. T., Loo, L., Chow, P. K., & Ngeow, J. (2023). Global Epidemiology and Genetics of Hepatocellular Carcinoma. Gastroenterology, 164(5), 766–782. https://doi.org/10.1053/j.gastro.2023.01.033

Tsunedomi, R., Yoshimura, K., Kimura, Y., Nishiyama, M., Fujiwara, N., Matsukuma, S., Kanekiyo, S., Matsui, H., Shindo, Y., Watanabe, Y., Tokumitsu, Y., Yoshida, S., Iida, M., Suzuki, N., Takeda, S., Ioka, T., Hazama, S., & Nagano, H. (2022). Elevated expression of RAB3B plays important roles in chemoresistance and metastatic potential of hepatoma cells. BMC Cancer, 22(1). https://doi.org/10.1186/s12885-022-09370-1

Van Zijl, F., Zulehner, G., Petz, M., Schneller, D., Kornauth, C., Hau, M., Machat, G., Grubinger, M., Huber, H., & Mikulits, W. (2009). Epithelial–Mesenchymal Transition in Hepatocellular Carcinoma. Future Oncology, 5(8), 1169–1179. https://doi.org/10.2217/fon.09.91

Vogel, A., & Saborowski, A. (2019). Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma. Cancer Treatment Reviews, 82, 101946. https://doi.org/10.1016/j.ctrv.2019.101946

Wang, Q., Liu, J., Chen, Z., Zheng, J., Wang, Y., & Dong, J. (2023). Targeting metabolic reprogramming in hepatocellular carcinoma to overcome therapeutic resistance: A comprehensive review. Biomedicine & Pharmacotherapy, 170, 116021. https://doi.org/10.1016/j.biopha.2023.116021

Wang, M., Liu, H., Zhang, X., Zhao, W., Lin, X., Zhang, F., Li, D., Xu, C., Xie, F., Wu, Z., Yang, Q., & Li, X. (2021). Lack of MOF decreases susceptibility to hypoxia and promotes multidrug resistance in hepatocellular carcinoma via HIF-1Α. Frontiers in Cell and Developmental Biology, 9. https://doi.org/10.3389/fcell.2021.718707

Wang, M., Huang, C., Su, Y., Yang, C., Xia, Q., & Xu, D. (2017). Astragaloside II sensitizes human hepatocellular carcinoma cells to 5-fluorouracil via suppression of autophagy. Journal of Pharmacy and Pharmacology, 69(6), 743–752. https://doi.org/10.1111/jphp.12706

Woo, H. G., Wang, X. W., Budhu, A., Kim, Y. H., Kwon, S. M., Tang, Z., Sun, Z., Harris, C. C., & Thorgeirsson, S. S. (2010). Association of TP53 Mutations with Stem Cell-Like Gene Expression and Survival of Patients with Hepatocellular Carcinoma. Gastroenterology, 140(3), 1063-1070.e8. https://doi.org/10.1053/j.gastro.2010.11.034

Yan, L., Xu, F., & Dai, C. (2018). Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma. Journal of Experimental & Clinical Cancer Research, 37(1). https://doi.org/10.1186/s13046-018-0887-z

Yao, Q., Chen, Y., & Zhou, X. (2019). The roles of microRNAs in epigenetic regulation. Current Opinion in Chemical Biology, 51, 11–17. https://doi.org/10.1016/j.cbpa.2019.01.024

Yuan, P., Cao, W., Zang, Q., Li, G., Guo, X., & Fan, J. (2016). The HIF-2α-MALAT1-miR-216b axis regulates multi-drug resistance of hepatocellular carcinoma cells via modulating autophagy. Biochemical and Biophysical Research Communications, 478(3), 1067–1073. https://doi.org/10.1016/j.bbrc.2016.08.065

Zemek, R. M., Chin, W. L., Nowak, A. K., Millward, M. J., Lake, R. A., & Lesterhuis, W. J. (2020). Sensitizing the Tumor Microenvironment to Immune Checkpoint Therapy. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.00223

Zhang, D., Liu, J., Tang, M., Yiu, A., Cao, H., Jiang, L., Chan, J. Y., Tian, H., Fung, K., & Ye, W. (2012). Bufotalin from Venenum Bufonis inhibits growth of multidrug resistant HepG2 cells through G2/M cell cycle arrest and apoptosis. European Journal of Pharmacology, 692(1–3), 19–28. https://doi.org/10.1016/j.ejphar.2012.06.045

Zhao, X., Li, L., Wang, X., Fu, R., Lv, Y., Jin, W., Meng, C., Chen, G., Huang, L., & Zhao, K. (2016). Inhibition of Snail family Transcriptional Repressor 2 (SNAI2) enhances multidrug resistance of hepatocellular carcinoma cells. PLoS ONE, 11(10), e0164752. https://doi.org/10.1371/journal.pone.0164752

• PDF

Copyright (c) 2025 Sidra Javed, Isbah Ashfaq, Mehak Shahid, Asima Tayyeb (Author)

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.