<br>p53/Sp1/MUC5AC轴在肺腺癌肿瘤发生和进展中的分子洞察,Clinical and Experimental Pharmacology and Physiology

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p53/Sp1/MUC5AC轴在肺腺癌肿瘤发生和进展中的分子洞察
Clinical and Experimental Pharmacology and Physiology ( IF 2.4 ) Pub Date : 2022-09-04 , DOI: 10.1111/1440-1681.13720
Jing Zhang ₁ , Wenjuan He ₁ , Xiangying Hu ₂ , Xia Fang ₁ , Guosheng Wang ₁ , Rongjuan Tang ₁ , Ping Zhang ₃ , Qiang Li ₁

Affiliation

分泌性粘蛋白 MUC5AC 在各种癌症的肿瘤发生和进展过程中的异常表达已被记录。然而，目前对于MUC5AC在肺腺癌中的功能知之甚少。本研究重点关注MUC5AC的促癌作用及其在肺腺癌中的调节机制。首先，通过免疫组织化学评估了 NSCLC 组织微阵列中的 MUC5AC 表达。 Kaplan-Meier 分析用于阐明 MUC5AC 的预后价值。随后，使用小干扰RNA和小发夹RNA敲低肺ADC细胞系中的MUC5AC，通过体外功能测定和异种移植小鼠模型阐明其在肺腺癌肿瘤发生和进展中的作用。最后，通过双荧光素酶报告确定了p53/Sp1/MUC5AC轴的调控机制。我们发现 MUC5AC 在肺 ADC 组织和细胞系中表达上调，尤其是在KRAS突变病例中，并且与不良预后相关。 MUC5AC 基因沉默导致细胞增殖、侵袭和迁移减少。此外，MUC5AC 的敲除导致上皮-间质转化的逆转。此外，MUC5AC 的下调可减少小鼠模型中的肿瘤发生。最后，我们发现Sp1和p53在MUC5AC基因表达的调节中具有拮抗作用。我们的研究结果表明，MUC5AC 高表达可促进肿瘤发生和肺 ADC 的进展。肺 ADC 中 p53 基因失活和 Sp1 过表达都可能增强 MUC5AC 表达，特别是在KRAS突变病例中。鉴于KRAS驱动的肺 ADC 缺乏有效的药物靶向方法，针对 MUC5AC 等下游效应器的疗法可能具有巨大的前景。

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Molecular insight of p53/Sp1/MUC5AC axis in the tumorigenesis and progression of lung adenocarcinoma

The aberrant expression of secretory mucin MUC5AC has been documented during the tumourigenesis and progression of various cancers. However, little is currently known on the function of MUC5AC in lung adenocarcinoma. The present study focused on the tumour-promoting role of MUC5AC and its regulatory mechanisms in lung adenocarcinoma. Firstly, MUC5AC expression was evaluated in NSCLC tissue microarrays by immunohistochemistry. Kaplan–Meier analysis were used to clarify the prognostic value of MUC5AC. Subsequently, small interfering RNA and small hairpin RNA were used to knockdown MUC5AC in lung ADC cell lines to elucidate its role in tumorigenesis and progression of lung adenocarcinoma via in vitro functional assays and xenograft mouse models. Finally, the regulatory mechanisms underlying p53/Sp1/MUC5AC axis were identified through dual-luciferase report. We found that MUC5AC was upregulated in lung ADC tissues and cell lines, especially in KRAS-mutant cases and correlated with poor prognosis. MUC5AC gene silencing resulted in reduced cell proliferation, invasion and migration. Furthermore, knockdown of MUC5AC led to reversion of the epithelial–mesenchymal transition. Additionally, downregulation of MUC5AC reduced tumourigenesis in mouse models. Finally, we found an antagonistic role between Sp1 and p53 in the regulation of MUC5AC gene expression. Our findings suggest that high MUC5AC expression promotes tumourigenesis and progression of lung ADC. Both p53 gene inactivation and Sp1 overexpression in lung ADC may enhance MUC5AC expression, especially in KRAS-mutated cases. Given the paucity of efficient drug-targeted approaches of KRAS-driven lung ADCs, therapies directed at downstream effectors such as MUC5AC could have huge prospects.

更新日期：2022-09-04

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