Dataset Information

RBBP4 Enhances Platinum Chemo Resistance in Lung Adenocarcinoma.

ABSTRACT:

Background

The majority of lung cancers are adenocarcinomas, with the proportion being 40%. The patients are mostly diagnosed in the middle and late stages with metastasis and easy recurrence, which poses great challenge to the treatment and prognosis. Platinum-based chemotherapy is a primary treatment for adenocarcinoma, which frequently causes drug resistance. As a result, it is important to uncover the mechanisms of the chemoresponse of adenocarcinoma to platinum-based chemotherapy.

Methods

The genes from the dataset GSE7880 were gathered into gene modules with the assistance of weighted gene coexpression network analysis (WGCNA), the gene trait significance absolute value (|GS|), and gene module memberships (MM). The genes from hub gene modules were calculated with a protein-protein interaction (PPI) network analysis in order to obtain a screening map of hub genes. The hub genes with both a high |GS| and MM and a high degree were selected. Furthermore, genes in the hub gene modules also went through a Gene Ontology (GO) functional enrichment analysis.

Results

11 hub genes in four hub gene modules (LY86, ACTR2, CDK2, CKAP4, KPNB1, RBBP4, SMAD4, MYL6, RPS27, TSPAN2, and VAMP2) were chosen as the significant hub genes. Through the GO function enrichment analysis, it was indicated that four modules were abundant in immune system functions (floralwhite), amino acid biosynthetic process (lightpink4), cell chemotaxis (navajowhite2), and targeting protein (paleturquoise). Four hub genes with the highest |GS| were verified by prognostic analysis.

SUBMITTER: Wang N

PROVIDER: S-EPMC7811416 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

RBBP4 Enhances Platinum Chemo Resistance in Lung Adenocarcinoma.

Wang Nianwu N Wang Wei W Mao Wenli W Kuerbantayi Nazuke N Jia Nuan N Chen Yan Y Zhou Fang F Yin Li L Wang Yukun Y

BioMed research international 20210109

<h4>Background</h4>The majority of lung cancers are adenocarcinomas, with the proportion being 40%. The patients are mostly diagnosed in the middle and late stages with metastasis and easy recurrence, which poses great challenge to the treatment and prognosis. Platinum-based chemotherapy is a primary treatment for adenocarcinoma, which frequently causes drug resistance. As a result, it is important to uncover the mechanisms of the chemoresponse of adenocarcinoma to platinum-based chemotherapy.<h ...[more]

PMID: 33506032

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Project description:BACKGROUND:The platinum-based chemotherapy is the first-line regimen for the treatment of Non-small cell lung cancer (NSCLC). However, the therapeutic efficiency is largely limited by tenacious chemo-insensitivity that results in inferior prognosis in a cohort of patients. It has been known that KIAA1522 is aberrantly expressed and implicated in several types of solid tumors including NSCLC. Nowadays, knowledge about this gene is quite limited. Here, we aimed to identify the role of KIAA1522 in lung adenocarcinomas, and the molecular events that underlie KIAA1522-mediated chemoresistance to the platinum. METHODS:Immunohistochemistry were used to detect KIAA1522 expression in clinical NSCLC samples. Then, the survival analyses were performed to assess the link between KIAA1522 expression and overall survival or therapeutic outcome. In vivo depletion of KIAA1522 in adenocarcinoma cells were achieved by adeno-associated virus-mediated sgRNA/Cre delivery into the conditional KrasG12D/Cas9 expressed mice, which were designated to identify the roles of KIAA1522 in tumorigenesis and/or chemotherapy responses. The effects of KIAA1522 and downstream molecular events were studied by pharmacology in mice model and assays using in vitro cultured cells. The clinical relevance of our findings was examined by data-mining of online datasets from multiple cohorts. RESULTS:The clinical evidences reveal that KIAA1522 independently predicts both the overall survival and the outcome of platinum-based chemotherapy in lung adenocarcinomas. By using a KrasG12D-driven murine lung adenocarcinoma model and performing in vitro assays, we demonstrated that KIAA1522 is a critical positive regulator of lung adenocarcinoma and a modulator of cisplatin response. KIAA1522 potentiates the TNF?-TNFR2-NF?B signaling which in turn intensifies recalcitrance to cisplatin treatment. These results were further manifested by integrative bioinformatic analyses of independent datasets, in which KIAA1522 is tightly associated with the activity of TNF?-NF?B pathway and the cisplatin-resistant gene signatures. More strikingly, overexpression of KIAA1522 counteracts the cisplatin-induced tumor growth arrest in vivo, and this effect can be remarkably diminished by the disruption of NF?B activity. CONCLUSION:High expression of KIAA1522 is turned out to be an indicator of dismal effectiveness of platinum-based therapy in lung adenocarcinomas. KIAA1522 hyperactivates TNF?-NF?B signaling to facilitate resistance to platinum reagents. Targeting NF?B signaling through small molecule inhibitors may be a rational strategy to conquer chemoresistance and synergize platinum-based chemotherapy in KIAA1522 overexpressed lung adenocarcinomas.

Dataset Information

RBBP4 Enhances Platinum Chemo Resistance in Lung Adenocarcinoma.

Background

Methods

Results

Publications

RBBP4 Enhances Platinum Chemo Resistance in Lung Adenocarcinoma.

Similar Datasets

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