Gel-forming mucin MUC5B is significantly deregulated in lung adenocarcinoma (LUAD), however, its role in tumor progression is not yet clearly understood. Here, we used an integrated computational-pipeline-initiated with gene expression analysis followed by network, functional-enrichment, O-linked glycosylation analyses, mutational profiling, and immune cell infiltration estimation to functionally characterize MUC5B gene in LUAD. Thereafter, clinical biomarker validation was supported by the overall survival (OA) and comparative expression profiling across clinical stages using computational algorithms. The gene expression profile of LUAD identified MUC5B to be significantly up-regulated (logFC: 2.36; p-value: 0.01). Network analysis on LUAD interactome screened MUC5B-related genes, having key enrichment in immune suppression and O-linked glycosylation with serine–threonine-rich tandem repeats being highly glycosylated. Furthermore, positive correlation of mutant MUC5B with immune cells in tumor microenvironment (TME) such as cancer-associated fibroblasts and myeloid-derived suppressor cells indicates TME-mediated tumor progression. The positive correlation with immune inhibitors suggested the enhanced tumor proliferation mediated by MUC5B. Structural stability due to genetic alterations identified overall rigid N–H-backbone dynamics (S²: 0.756), indicating an overall stable mutant protein. Moreover, the low median OA (<50 months) with a hazard ratio of 1.4 and clinical profile of MUC5B gene showed high median expression corresponding to lymph node (N2) and tumor (T3) stages. Our study concludes by highlighting the functional role of O-glycosylated and mutant MUC5B in promoting LUAD by immune suppression. Further, clinical gene expression validation of MUC5B suggests its potential role as a diagnostic biomarker for LUAD metastasis.

中文翻译：

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阐明 MUC5B 在进展性肺腺癌中的分子作用：早期诊断的前景

凝胶形成粘蛋白 MUC5B 在肺腺癌 (LUAD) 中显着失调，然而，其在肿瘤进展中的作用尚不清楚。在这里，我们使用集成的计算管道启动基因表达分析，然后进行网络、功能富集、O-连接糖基化分析、突变分析和免疫细胞浸润估计，以对 LUAD 中的 MUC5B 基因进行功能表征。此后，临床生物标志物验证得到了总体生存率 (OA) 和使用计算算法跨临床阶段的比较表达谱的支持。LUAD 的基因表达谱鉴定 MUC5B 显着上调（logFC：2.36；p值：0.01）。LUAD相互作用组网络分析筛选出MUC5B相关基因，在免疫抑制和O-连接糖基化方面具有关键富集，富含丝氨酸-苏氨酸的串联重复序列高度糖基化。此外，突变型MUC5B与肿瘤微环境（TME）中的免疫细胞（例如癌症相关成纤维细胞和骨髓源性抑制细胞）呈正相关，表明TME介导的肿瘤进展。与免疫抑制剂的正相关表明MUC5B介导的肿瘤增殖增强。由于遗传改变而导致的结构稳定性确定了整体刚性的 N-H-主链动力学 (S ² : 0.756)，表明整体稳定的突变蛋白。此外，风险比为1.4的低中位OA（<50个月）和MUC5B基因的临床特征显示出与淋巴结（N2）和肿瘤（T3）阶段相对应的高中位表达。我们的研究最后强调了 O-糖基化和突变体 MUC5B 在通过免疫抑制促进 LUAD 中的功能作用。此外，MUC5B 的临床基因表达验证表明其作为 LUAD 转移的诊断生物标志物的潜在作用。