Li Mengxuan, Che Nan, Feng Ying, Liu Xingzhe, Piao Lihua, Xuan Yanhua, Jin Yu
Human anatomy and histoembryology, Yanbian University College of Medicine, Yanji, China; Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, China.
Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, China; Department of Pathology, Yanbian University College of Medicine, Yanji, China.
Exp Mol Pathol. 2022 Apr;125:104755. doi: 10.1016/j.yexmp.2022.104755. Epub 2022 Mar 10.
Several studies have demonstrated that B7-H4 is highly expressed in a variety of cancers and often affects tumor development. However, its role in cancer stemness and epithelial-to-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) has not been reported. Here, we investigated the relationship between B7-H4 expression and cancer stemness and EMT by immunohistochemistry in 106 NSCLC tissues obtained from patients. The results confirmed that B7-H4 is highly expressed in NSCLC tissues and closely correlated with the expression of EMT-related proteins (Snail, Vimentin) and cancer stemness-related proteins (SOX2, SOX9, and CD44). Immunofluorescence assay indicated that B7-H4 colocalized with SOX2 and SOX9 in the nuclei of NSCLC cells. Additionally, upon knocking down B7-H4, the expression of SOX2, SOX9, and CD44, as well as of Snail and Vimentin was inhibited, whereas E-cadherin expression was enhanced in NSCLC cells. Meanwhile, inhibiting the expression of B7-H4 resulted in reduced invasion and migration ability of NSCLC cells. Mechanistically, silencing B7-H4 activated the adenosine monophosphate-activated protein kinase /mammalian target of rapamycin signaling, which in turn, negatively regulated cell proliferation, stemness, and migration. In conclusion, our results suggest that B7-H4 expression is high in NSCLC tissues, and it has an effect on EMT and cancer stemness. This further suggests that B7-H4 has a potential role in promoting the progression of NSCLC and thereby could be a potential therapeutic target in NSCLC treatment.
多项研究表明，B7-H4在多种癌症中高表达，且常常影响肿瘤发展。然而，其在非小细胞肺癌（NSCLC）的癌症干性及上皮-间质转化（EMT）中的作用尚未见报道。在此，我们通过免疫组织化学方法研究了106例NSCLC患者组织中B7-H4表达与癌症干性及EMT之间的关系。结果证实，B7-H4在NSCLC组织中高表达，且与EMT相关蛋白（Snail、波形蛋白）及癌症干性相关蛋白（SOX2、SOX9和CD44）的表达密切相关。免疫荧光分析表明，B7-H4与SOX2和SOX9在NSCLC细胞核中共定位。此外，敲低B7-H4后，NSCLC细胞中SOX2、SOX9和CD44以及Snail和波形蛋白的表达受到抑制，而E-钙黏蛋白表达增强。同时，抑制B7-H4的表达导致NSCLC细胞的侵袭和迁移能力降低。机制上，沉默B7-H4激活了腺苷单磷酸激活的蛋白激酶/雷帕霉素哺乳动物靶标信号通路，进而负向调节细胞增殖、干性和迁移。总之，我们的结果表明，B7-H4在NSCLC组织中表达较高，且对EMT和癌症干性有影响。这进一步提示，B7-H4在促进NSCLC进展中具有潜在作用，因此可能是NSCLC治疗中的一个潜在治疗靶点。
