Ye Chunshui, Chong Wei, Liu Yuan, Zhu Xingyu, Ren Huicheng, Xu Kang, Xie Xiaozhou, Du Fengying, Zhang Zihao, Wang Mingfei, Ma Tianrong, Shang Liang, Li Leping, Chen Hao
Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University Jinan, Shandong, China.
Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan, Shandong, China.
Am J Cancer Res. 2023 Jul 15;13(7):2886-2905. eCollection 2023.
Lung adenocarcinoma (LUAD) is the most common type of lung cancer. LRP1B was initially identified as a cancer suppressor in several cancers. However, the potential biological phenotypes and molecular mechanisms of LRP1B in LUAD have not been fully investigated. In our study, we showed that the expression of LRP1B in LUAD tissues was lower than that in normal tissues. Knockdown of LRP1B markedly enhanced malignancy of LUAD cells. Genomic analysis indicated that the population expressing low-levels of LRP1B had higher genomic instability, which accounted for a larger proportion of aneuploidy and inflammation subtyping. Enrichment analysis of bulk and cell-line transcriptomic data both showed that the low expression of LRP1B could induce the activation of IL-6-JAK-STAT3, chemokine, cytokine, and other inflammation signaling pathways. Moreover, our findings revealed that knockdown LRP1B enhanced the secretion of IL-6 and IL-8, as confirmed by ELISA assays. Further validation using PCR and WB confirmed that downregulation of LRP1B mRNA significantly upregulated the activity of the IL-6-JAK-STAT3 pathway. Collectively, this study highlights LRP1B as a tumor suppressor gene and reveals that LRP1B knockdown promotes malignant progression in LUAD by inducing inflammation through the IL-6-JAK-STAT3 pathway.
肺腺癌（LUAD）是最常见的肺癌类型。LRP1B最初在几种癌症中被鉴定为一种抑癌基因。然而，LRP1B在LUAD中的潜在生物学表型和分子机制尚未得到充分研究。在我们的研究中，我们发现LUAD组织中LRP1B的表达低于正常组织。敲低LRP1B显著增强了LUAD细胞的恶性程度。基因组分析表明，低水平表达LRP1B的群体具有更高的基因组不稳定性，这在非整倍体和炎症亚型中占更大比例。对批量和细胞系转录组数据的富集分析均表明，LRP1B的低表达可诱导IL-6-JAK-STAT3、趋化因子、细胞因子和其他炎症信号通路的激活。此外，我们的研究结果显示，通过ELISA检测证实，敲低LRP1B可增强IL-6和IL-8的分泌。使用PCR和WB进行的进一步验证证实，LRP1B mRNA的下调显著上调了IL-6-JAK-STAT3通路的活性。总的来说，本研究强调LRP1B作为一种肿瘤抑制基因，并揭示敲低LRP1B通过IL-6-JAK-STAT3通路诱导炎症，从而促进LUAD的恶性进展。
