Han Shuyan, Tian Zhihua, Tian Huifang, Han Haibo, Zhao Jun, Jiao Yanna, Wang Chunli, Hao Huifeng, Wang Shan, Fu Jialei, Xue Dong, Sun Hong, Li Pingping
Department of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Central Laboratory, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Cell Death Discov. 2023 Jun 10;9(1):181. doi: 10.1038/s41420-023-01476-0.
Hepatoma-derived growth factor (HDGF) expression is associated with poor prognosis in non-small cell lung cancer (NSCLC); however, whether HDGF affects gefitinib resistance in NSCLC remains unknown. This study aimed to explore the role of HDGF in gefitinib resistance in NSCLC and to discover the underlying mechanisms. Stable HDGF knockout or overexpression cell lines were generated to perform experiments in vitro and in vivo. HDGF concentrations were determined using an ELISA kit. HDGF overexpression exacerbated the malignant phenotype of NSCLC cells, while HDGF knockdown exerted the opposite effects. Furthermore, PC-9 cells, which were initially gefitinib-sensitive, became resistant to gefitinib treatment after HDGF overexpression, whereas HDGF knockdown enhanced gefitinib sensitivity in H1975 cells, which were initially gefitinib-resistant. Higher levels of HDGF in plasma or tumor tissue also indicated gefitinib resistance. The effects of HDGF on promoting the gefitinib resistance were largely attenuated by MK2206 (Akt inhibitor) or U0126 (ERK inhibitor). Mechanistically, gefitinib treatment provoked HDGF expression and activated the Akt and ERK pathways, which were independent of EGFR phosphorylation. In summary, HDGF contributes to gefitinib resistance by activating the Akt and ERK signaling pathways. The higher HDGF levels may predict poor efficacy for TKI treatment, thus it has the potential to serve as a new target for overcoming tyrosine kinase inhibitor resistance in combating NSCLC.
肝癌衍生生长因子（HDGF）的表达与非小细胞肺癌（NSCLC）的不良预后相关；然而，HDGF是否影响NSCLC对吉非替尼的耐药性仍不清楚。本研究旨在探讨HDGF在NSCLC对吉非替尼耐药中的作用，并发现其潜在机制。构建了稳定的HDGF基因敲除或过表达细胞系，进行体内外实验。使用ELISA试剂盒测定HDGF浓度。HDGF过表达加剧了NSCLC细胞的恶性表型，而HDGF基因敲低则产生相反的效果。此外，最初对吉非替尼敏感的PC-9细胞在HDGF过表达后对吉非替尼治疗产生耐药性，而HDGF基因敲低增强了最初对吉非替尼耐药的H1975细胞对吉非替尼的敏感性。血浆或肿瘤组织中较高水平的HDGF也表明存在吉非替尼耐药。MK2206（Akt抑制剂）或U0126（ERK抑制剂）在很大程度上减弱了HDGF促进吉非替尼耐药的作用。机制上，吉非替尼治疗可引发HDGF表达并激活Akt和ERK通路，这与EGFR磷酸化无关。总之，HDGF通过激活Akt和ERK信号通路导致吉非替尼耐药。较高的HDGF水平可能预示TKI治疗效果不佳，因此它有可能成为克服NSCLC中酪氨酸激酶抑制剂耐药性的新靶点。
