Heat shock protein family A member 1A expression is increased in hepatocellular carcinoma and mediates sorafenib resistance

Abstract

Abstract: Objective: To explore the expression of heat shock protein family A member 1A (HSPA1A) in hepatocellular carcinoma (HCC) patients and whether it is involved in sorafenib resistance mechanism.
Methods: The 152 patients with HCC admitted to our hospital from March 2022 to March 2024 were selected. Hub genes mediating sorafenib resistance were screened by three microarray data from the Gene Expression Omnibus database. Resistance genes were further explored by The Cancer Genomic Atlas-HCC cohort, immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (RT-qPCR), western blot (WB) analyses, and cellular function. The correlation between HSPA1A expression and sorafenib 50% inhibitory concentration(IC50) was analysed by drug sensitivity. The relationship between HSPA1A expression and autophagy signalling was analysed by single-sample single sample gene set enrichment analysis (ssGSEA) algorithm.
Results: HSPA1A expression was significantly higher in both sorafenib-treated and resistance tissues (P<0.05). IHC, RT-qPCR and WB confirmed that HSPA1A expression levels were higher in sorafenib-resistant patients than in responding patients (all P<0.05). Gene Expression Profiling Interactive Analysis database and IHC showed significantly higher HSPA1A protein expression in HCC tissues. Clinical cohorts and the Kaplan-Meier plotter database confirmed lower overall survival rate and relapse-free survival rate in patients with high HSPA1A expression (all P<0.05). CCK-8, clone formation, scratch and invasion assays confirmed that knockdown of HSPA1A significantly inhibited Huh-7 and MHCC97-L cell viability, proliferation, migration and invasion ability (all P<0.05).CCK-8 assay showed that the IC50 of sorafenib in Huh-7 and MHCC97-L cells knocked down by HSPA1A decreased by 17.4% and 19.3% (all P<0.05), increasing the therapeutic sensitivity of sorafenib. ssGSEA analysis showed that high HSPA1A mRNA expression inhibited autophagy activity (P<0.05).
Conclusion: HSPA1A expression is increased in HCC and may be involved in the mechanism of sorafenib resistance, and the underlying mechanism may be related to autophagy signalling. Further experiments are needed to explore the potential mechanism of HSPA1A in HCC and provide new strategies to overcome sorafenib resistance.

Key words: HSPA1A, Hepatocellular carcinoma, Sorafenib, Drug resistance, Autophagy

Yang Li, Lu Xue. Heat shock protein family A member 1A expression is increased in hepatocellular carcinoma and mediates sorafenib resistance[J]. Electronic Journal of Liver Tumor, 2025, 12(2): 14-21.

References

[1] SON Y, SHIN N R, KIM S H, et al.Fibrinogen-like protein 1 modulates sorafenib resistance in human hepatocellular carcinoma cells[J]. Int J Mol Sci, 2021, 22(10): 5330.
[2] TANG W, CHEN Z, ZHANG W, et al.The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects[J]. Signal Transduct Target Ther, 2020, 5(1): 87.
[3] TAN X P, XIONG B H, ZHANG Y X, et al.FXYD5 promotes sorafenib resistance through the Akt/mTOR signaling pathway in hepatocellular carcinoma[J]. Eur J Pharmacol, 2022, 931: 175186.
[4] LU Y, CHAN Y T, TAN H Y, et al.Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma[J]. J Exp Clin Cancer Res, 2022, 41(1): 3.
[5] ZHU Y J, ZHENG B, WANG H Y, et al.New knowledge of the mechanisms of sorafenib resistance in liver cancer[J]. Acta Pharmacol Sin, 2017, 38(5): 614-622.
[6] MERY B, VALLARD A, ROWINSKI E, et al.High-throughput sequencing in clinical oncology: from past to present[J]. Swiss Med Wkly, 2019, 149: w20057.
[7] WU C, QI X, QIU Z, et al.Low expression of KIF20A suppresses cell proliferation, promotes chemosensitivity and is associated with better prognosis in HCC[J]. Aging (Albany NY), 2021, 13(18): 22148-22163.
[8] CHENG Z, WEI-QI J, JIN D.New insights on sorafenib resistance in liver cancer with correlation of individualized therapy[J]. Biochim Biophys Acta Rev Cancer, 2020, 1874(1): 188382.
[9] OGBODO E, MICHELANGELI F, WILLIAMS J H H. Exogenous heat shock proteins HSPA1A and HSPB1 regulate TNF-α, IL-1β and IL-10 secretion from monocytic cells[J]. FEBS Open Bio, 2023, 13(10): 1922-1940.
[10] RINGELHAN M, PFISTER D, O'CONNOR T, et al. The immunology of hepatocellular carcinoma[J]. Nat Immunol, 2018, 19(3): 222-232.
[11] WANG B, LAN T, XIAO H, et al.The expression profiles and prognostic values of HSP70s in hepatocellular carcinoma[J]. Cancer Cell Int, 2021, 21(1): 286.
[12] SUN T, LIU H, MING L.Multiple roles of autophagy in the sorafenib resistance of hepatocellular carcinoma[J]. Cell Physiol Biochem, 2017, 44(2): 716-727.
[13] RUSSELL R C, GUAN K L.The multifaceted role of autophagy in cancer[J]. EMBO J, 2022, 41(13): e110031.
[14] DEBNATH J, GAMMOH N, RYAN K M.Autophagy and autophagy-related pathways in cancer[J]. Nat Rev Mol Cell Biol, 2023, 24(8): 560-575.
[15] SHI Y H, DING Z B, ZHOU J, et al.Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis[J]. Autophagy, 2011, 7(10): 1159-1172.
[16] ZHAI B, HU F, JIANG X, et al.Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma[J]. Mol Cancer Ther, 2014, 13(6): 1589-1598.
[17] TAI W T, SHIAU C W, CHEN H L, et al.Mcl-1-dependent activation of Beclin 1 mediates autophagic cell death induced by sorafenib and SC-59 in hepatocellular carcinoma cells[J]. Cell Death Dis, 2013, 4(2): e485.
[18] HE C, DONG X, ZHAI B, et al.MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway[J]. Oncotarget, 2015, 6(30): 28867-28881.