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Published on: September 16, 2019
Exploratory research on therapeutic agents combined with early diagnostic biomarkers for colorectal cancer
Qiming Liao1, Yulong Xue2, Yajiang Yu2
1Department of Medical Informatics and Computer, Zhengzhou Health College, Zhengzhou, Henan, China.
Introduction:
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Although diagnostic and therapeutic strategies have advanced, the molecular mechanisms driving CRC pathogenesis are not fully understood, highlighting the need for novel biomarkers and therapeutic agents.
Methods:
Integrated bioinformatics analyses of transcriptomic datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were performed to identify survival-associated differentially expressed genes (DEGs) in CRC (|log2FC| > 1.5, p < 0.05). These key DEGs were then used to query the L1000FWD, DGIdb, and CMap platforms to predict candidate small-molecule drugs. The top candidate was evaluated by molecular docking, and its anti-tumor effects were validated by MTT cell viability assays in CRC cell lines.
Results:
We identified 15 survival-associated DEGs-MELK, NFE2L3, MCM2, MAD2L1, AUNIP, CXCL3, GLDN, GREM2, ALDH1A1, CILP, FABP4, AOC3, CNN1, ANGPTL1, and DES-as potential early diagnostic biomarkers for CRC. Drug-repositioning analyses convergently highlighted SB-225002 as a promising therapeutic agent. Molecular docking showed high binding affinity of SB-225002 to multiple key targets. MTT assays demonstrated that SB-225002 exerted dose-dependent inhibitory effects on the proliferation of CRC cell lines (SW-480, DLD-1, and MC38), with IC50 values of 2.307 μM, 0.9456 μM, and 3.449 μM, respectively.
Discussion:
This study systematically delineates a novel panel of early-detection biomarkers for CRC and identifies SB-225002 as a repurposed candidate therapeutic agent. The integrative strategy combining multi-cohort transcriptomic analysis, drug-repositioning platforms, molecular docking, and experimental validation offers a feasible framework for discovering clinically actionable biomarkers and small-molecule therapies for CRC.
Insights
Researchers identified 15 novel biomarkers for early colorectal cancer (CRC) detection. They also found SB-225002 to be a promising drug candidate for treating CRC, showing significant anti-tumor effects in cell lines.
Area of Science:
- Oncology
- Bioinformatics
- Molecular Biology
Background:
- Colorectal cancer (CRC) is a major global health concern with high mortality rates.
- Current diagnostic and therapeutic approaches for CRC need improvement due to incomplete understanding of its molecular drivers.
- There is a critical need for novel biomarkers for early detection and effective therapeutic agents for CRC.
Purpose of the Study:
- To identify novel survival-associated genes as potential early diagnostic biomarkers for colorectal cancer (CRC).
- To discover potential small-molecule drugs for CRC treatment through drug-repositioning analyses.
- To validate the anti-tumor efficacy of candidate drugs in CRC cell lines.
Main Methods:
- Integrated bioinformatics analysis of transcriptomic datasets (TCGA, GEO) to identify differentially expressed genes (DEGs).
- Utilized L1000FWD, DGIdb, and CMap platforms for drug-repositioning based on identified DEGs.
- Performed molecular docking and MTT cell viability assays for drug validation.
Main Results:
- Identified 15 survival-associated DEGs (e.g., MELK, MCM2, CXCL3) as potential early CRC biomarkers.
- SB-225002 emerged as a top candidate drug with high binding affinity to key targets.
- SB-225002 demonstrated dose-dependent inhibition of CRC cell proliferation with low IC50 values.
Conclusions:
- A novel panel of early diagnostic biomarkers for CRC was identified.
- SB-225002 is a promising repurposed therapeutic agent for colorectal cancer.
- The integrative approach provides a framework for discovering actionable biomarkers and therapies for CRC.
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