Su Pengfei, Yu Tian, Zhang Yingjing, Huang Hongyun, Chen Moxi, Cao Can, Kang Weiming, Liu Yuqin, Yu Jianchun
Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
Cancer Cell Int. 2024 Aug 12;24(1):287. doi: 10.1186/s12935-024-03453-8.
Gastric cancer (GC) stands out as one of the most prevalent malignancies affecting the digestive system, characterized by a substantial incidence rate and mortality. Maternal embryonic leucine zipper kinase (MELK) has been implicated in the advancement of various cancer types and the modulation of the tumor microenvironment. This study aims to delve into the involvement of MELK in chemoresistance and the tumor microenvironment of GC.
The MELK expression was detected using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemistry. Lentiviral transfection was employed to establish stable cell lines with either overexpressed or silenced MELK. The impact of MELK on the chemoresistance of GC cells and the polarization of macrophages was investigated through in vitro and in vivo functional assays. Additionally, the correlation between MELK and the cytokines colony-stimulating factor 1 (CSF-1), as well as stromal macrophages, was analysed. The prognostic significance of MELK, CSF-1, and CD206 expression levels in clinical samples was further investigated.
MELK was found to be highly expressed in chemoresistant GC cells and tissues. Furthermore, both in vitro and in vivo assays indicated that MELK overexpression conferred chemoresistance in GC cells. Additionally, MELK overexpression was observed to induce M2 macrophage polarization via the CSF-1/JAK2/STAT3 pathway, thereby contributing to chemoresistance within the tumor microenvironment. The expression of MELK in GC tissues from neoadjuvant chemotherapy patients correlated positively with CSF-1 and CD206. Moreover, patients with higher expression levels of MELK, CSF-1, or CD206 exhibited significantly shorter OS and DFS rates.
Our investigation underscores the critical role of MELK in promoting chemoresistance and inducing M2 macrophage polarization in GC. It proposes novel targets and methods for the treatment of GC, as well as prognostic factors for neoadjuvant chemotherapy.
胃癌（GC）是影响消化系统的最常见恶性肿瘤之一，发病率和死亡率都很高。母源胚胎亮氨酸拉链激酶（MELK）与多种癌症类型的进展以及肿瘤微环境的调节有关。本研究旨在探讨MELK在GC的化疗耐药性和肿瘤微环境中的作用。
采用定量实时聚合酶链反应（qRT-PCR）、蛋白质免疫印迹法和免疫组织化学法检测MELK的表达。利用慢病毒转染建立MELK过表达或沉默的稳定细胞系。通过体外和体内功能试验研究MELK对GC细胞化疗耐药性和巨噬细胞极化的影响。此外，分析了MELK与细胞因子集落刺激因子1（CSF-1）以及基质巨噬细胞之间的相关性。进一步研究了临床样本中MELK、CSF-1和CD206表达水平的预后意义。
发现MELK在化疗耐药的GC细胞和组织中高表达。此外，体外和体内试验均表明，MELK过表达赋予GC细胞化疗耐药性。此外，观察到MELK过表达通过CSF-1/JAK2/STAT3途径诱导M2巨噬细胞极化，从而促进肿瘤微环境中的化疗耐药性。新辅助化疗患者GC组织中MELK的表达与CSF-1和CD206呈正相关。此外，MELK、CSF-1或CD206表达水平较高的患者的总生存期（OS）和无病生存期（DFS）显著缩短。
我们的研究强调了MELK在促进GC化疗耐药性和诱导M2巨噬细胞极化中的关键作用。它提出了治疗GC的新靶点和方法，以及新辅助化疗的预后因素。
