Comprehensive proteomic signature and identification of CDKN2A as a promising prognostic biomarker and therapeutic target of colorectal cancer

Abstract

BACKGROUND The carcinogenesis of colorectal cancer (CRC) involves many different molecules and multiple pathways, and the specific mechanism has not been elucidated until now. Existing studies on the proteomic signature profiles of CRC are relatively limited. Therefore, we herein aimed to provide a more comprehensive proteomic signature profile and discover new prognostic markers and therapeutic targets by performing proteomic analysis of CRC and paired normal tissues. AIM To investigate the proteomic signature and identify novel protein prognostic biomarkers of CRC. METHODS Cancer tissues and paired normal tissues were collected from 48 patients who underwent surgical removal at the China-Japan Friendship Hospital from January 2020 to June 2021. Data independent acquisition (DIA) quantitative proteomic analysis was performed using high-performance liquid chromatography–mass spectrometry/mass spectrometry (nano-UHPLC–MS/MS) to identify differentially expressed proteins, among which those with a P adj value ( t test, BH correction) < 0.05 and an absolute fold change (|log 2 FC|) > 2 were identified as potential markers. Differentially expressed proteins were selected by bioinformatics analysis and validated by immunohistochemical tissue microarrays, and their association with prognosis was further analyzed with the Gene Expression Profiling Interactive Analysis database to identify prognostic protein biomarkers of CRC. RESULTS Significantly differential protein expression was observed between cancer tissues and normal tissues. Compared with normal tissues, 1115 proteins were upregulated and 705 proteins were downregulated in CRC based on P adj < 0.05 and |log 2 FC| > 2, and bioinformatics analysis revealed that the differentially expressed proteins were involved in multiple biological processes associated with tumorigenesis, including ribosome biogenesis in eukaryotes, focal adhesion, extracellular matrix-receptor interactions and other tumor metabolism processes. Moreover, cyclin-dependent kinase inhibitor 2A (CDKN2A) expression was markedly upregulated in CRC, as validated by immunohistochemistry (0.228 vs 0.364, P = 0.0044), and was significantly enriched in tumor proliferation and signal transduction pathways such as the cell cycle and p53 signaling pathways. High CDKN2A expression was significantly correlated with poor prognosis ( P = 0.021). These results demonstrated that CDKN2A functions as a driver of CRC. CONCLUSION Our study provides a comprehensive proteomic signature of CRC and highlights CDKN2A as a potential powerful prognostic marker and precision therapeutic target.

Comprehensive analyses of cuproptosis-related gene CDKN2A on prognosis and immunologic therapy in human tumors

“…Concordant with this, recent convincing research also discovered that overexpressed CDKN2A was correlated with the poor prognosis in CRC. [ 21 , 34 , 37 ] These results revealed the potential of CDKN2A as an original prognostic predictor for some cancer types.…”

“…[32,33] Previous studies have revealed the suppressive roles of CDKN2A in some cancer types. [20,[34][35][36] Disruption of CDKN2A (deletion or methylation) has been reported to be a frequent event in tumorigenesis, which affected the clinical characteristics and patient outcomes. [14][15][16] Alhejaily and his colleagues revealed that silence of CDKN2A by deletion or methylation was correlated with worse clinical outcome in follicular lymphoma.…”

Network pharmacology and bioinformatics were used to construct a prognostic model and immunoassay of core target genes in the combination of quercetin and kaempferol in the treatment of colorectal cancer

“…In this research, network pharmacology and combined bioinformatics were used to analyze the targets of traditional Chinese medicine extracts quercetin and kaempferol, construct and screen the interaction network between drugs and CRC pathogenic genes, and finally screen three prognostic related genes: CDKN2A, SERPINE1, and MMP3 [74][75][76][77][78][79].…”

Identification and Verification of KEAP1-related genes and targets regulated by potential ingredients in KRAS mutant colorectal cancer

“…Furthermore, CDKN2A, SPP1 and FOS were strongly correlated with overall survival of COAD patients. It has reported that CDKN2A and SPP1 were initially identi ed as potential biomarkers and therapeutic targets of colon cancer metastasis [9,10]. CRC with liver metastasis (CRCLM), including SPP1 were signi cantly associated with CRCLM [11].…”