The role and mechanism of CHMP4C in poor prognosis and drug sensitivity of lung adenocarcinoma.

Background: Chromatin modified protein 4C (CHMP4C) is a charged polyvesicular protein (CHMP) that is involved in the composition of the endosomal sorting complex (ESCRT-III) required for transport III and promotes the necessary separation of daughter cells. CHMP4C involved in a wide variety of tumor progress, such as prostate cancer, cervical cancer and lung squamous cell carcinoma. However, the value of CHMP4C in lung adenocarcinoma has not been explored.

Methods: RNA-seq data and lung adenocarcinoma clinical information and corresponding pan-cancer were extracted from The Cancer Genome Atlas (TCGA) database to analyze CHMP4C expression and survival prognosis. The differential expression of CHMP4C was analyzed using the Human Protein Atlas (HPA) database. Clinical samples were collected to verify the differential expression of CHMP4C between lung adenocarcinoma and normal lung tissues via immunohistochemical (IHC) staining, qRT‒PCR and Western blotting. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of CHMP4C-related genes were performed. The correlation between CHMP4C and chemosensitivity was analyzed in the TCGA database. Then, qRT‒PCR, western blotting, transwell assays, cell proliferation assays, colony formation assays, wound healing assays, and cell cycle analysis were used to verify the possible regulatory mechanism involved. Molecular docking was used to predict small molecule compounds with potential roles in the treatment of lung adenocarcinoma.

Results: TIMER2.0 database analysis revealed that CHMP4C was differentially expressed in different tumors.Compared with that in healthy lung tissue, CHMP4C was significantly upregulated in lung adenocarcinoma tissue, and subsequent in vitro survival analysis revealed that CHMP4C expression has significant clinical prognostic value in lung adenocarcinoma. Enrichment analysis revealed that CHMP4C was mainly related to cell proliferation, cell migration, and the PI3K-Akt signaling pathway, etc. Overexpression of CHMP4C was associated with sensitivity to chemotherapy. Knocking down CHMP4C can significantly inhibit the proliferation, migration and invasion of lung adenocarcinoma cells and prolong the G0/G1 phase of the cell cycle. Molecular docking predicts 10 key drugs that may be used for the treatment of lung adenocarcinoma.

Conclusions: CHMP4C is highly expressed in a variety of tumors. We demonstrated that CHMP4C expression may be associated with the occurrence, development, prognosis and chemotherapy sensitivity in patients with lung adenocarcinoma. These findings may open up new research directions and development opportunities for the treatment of lung adenocarcinoma.