Open Access

ARTICLE

Apatinib modulates sorafenib-resistant hepatocellular carcinoma through inhibiting the EGFR/JNK/ERK signaling pathway

DEXUE FAN^1,#, WEI SU^2,#, ZHAOWEN BI³, XINXING WANG¹, XIANWEN XU¹, MINGZE MA⁴, LICHAO ZHU⁵, ZHENHAI ZHANG^1,3,*, JUNLIN GAO^2,*

1 Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
2 Liver Gall Bladder and Pancreatic Surgery Ward, Qinghai Red Cross Hospital, Xining, 810001, China
3 Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China
4 Departments of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
5 Department of Pediatric Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China

* Corresponding Authors: ZHENHAI ZHANG. Email: ; JUNLIN GAO. Email:
# These two authors contributed equally to this work

(This article belongs to the Special Issue: Signaling Pathway Crosstalk in Malignant Tumors: Molecular Targets and Combinatorial Therapeutics)

Oncology Research 2025, 33(6), 1459-1472. https://doi.org/10.32604/or.2025.060407

Received 31 October 2024; Accepted 03 January 2025; Issue published 29 May 2025

Abstract

Objectives: Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma (HCC) patients. However, the underlying mechanism remains ambiguous. The study aimed to explore the efficacy of apatinib in sorafenib-resistant HCC and the underlying mechanism both in vitro and in vivo. Methods: After observing epithelial-mesenchymal transformation (EMT) changes in HepG2 and HepG2/Sorafenib cells, we treated them with varying concentrations of apatinib to assess its impact on sorafenib-resistant HCC. Subsequently, specific inhibitors of c-Jun N-terminal kinase (JNK, SP600125) and extracellular signal-regulated kinase (ERK, PD98059) were introduced to investigate whether apatinib influenced sorafenib-resistant HCC via modulation of the epidermal growth factor receptor (EGFR)/JNK/ERK signaling pathway in vitro and in vivo. Biological behavior changes were assessed through cell counting kit-8 (CCK-8), colony formation, transwell, and immunofluorescence tests. Simultaneously, Western blot analysis was conducted to elucidate the expression of proteins associated with EMT and the EGFR/JNK/ERK signaling pathway. Results: The HepG2/Sorafenib cells exhibited greater resistance to sorafenib compared to HepG2 cells, and sorafenib-resistant HCC was characterized by EMT changes. Apatinib demonstrated concentration-dependent inhibition of biological behaviors in HepG2/Sorafenib cells, with minimal impact on HepG2 cells. Additionally, apatinib had a pronounced effect on the expression of EMT-related proteins in sorafenib-resistant cells similar to that in sorafenib-sensitive cells. Furthermore, there was a dose-dependent reduction in the expression of proteins associated with the EGFR/JNK/ERK pathway in apatinib-treated groups. Notably, SP600125 and PD98059 contributed to the inhibition of EMT and EGFR/JNK/ERK pathway-related proteins by apatinib in sorafenib-resistant HCC. Conclusion: Apatinib potentially hindered the progression of sorafenib-resistant HCC by suppressing both EMT and the EGFR/JNK/ERK pathway.

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