@Article{or.2025.060407,
AUTHOR = {DEXUE FAN, WEI SU, ZHAOWEN BI, XINXING WANG, XIANWEN XU, MINGZE MA, LICHAO ZHU, ZHENHAI ZHANG, JUNLIN GAO},
TITLE = {Apatinib modulates sorafenib-resistant hepatocellular carcinoma through inhibiting the EGFR/JNK/ERK signaling pathway},
JOURNAL = {Oncology Research},
VOLUME = {33},
YEAR = {2025},
NUMBER = {6},
PAGES = {1459--1472},
URL = {http://www.techscience.com/or/v33n6/61345},
ISSN = {1555-3906},
ABSTRACT = { <b>Objectives:</b> 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 <i>in vitro</i> and <i>in vivo</i>.  <b>Methods:</b> 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 <i>in vitro</i> and <i>in vivo</i>. 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.  <b>Results:</b> 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.  <b>Conclusion:</b> Apatinib potentially hindered the progression of sorafenib-resistant HCC by suppressing both EMT and the EGFR/JNK/ERK pathway.},
DOI = {10.32604/or.2025.060407}
}