REG4 promotes the proliferation and anti-apoptosis of cancer
Hua-Chuan Zheng1, Hang Xue1, Cong-Yu Zhang2
1Department of Oncology and Central Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, China.
Abstract:
Regenerating islet-derived 4 (REG4) gene was discovered by high-throughput sequencing of ulcerative colitis cDNA libraries. REG4 is involved in infection and inflammation by enhancing macrophage polarization to M2, via activation of epidermal growth factor receptor (EGFR)/Akt/cAMP-responsive element binding and the killing inflammatory Escherichia coli, and closely linked to tumorigenesis. Its expression was transcriptionally activated by caudal type homeobox 2, GATA binding protein 6, GLI family zinc finger 1, SRY-box transcription factor 9, CD44 intracytoplasmic domain, activating transcription factor 2, and specificity protein 1, and translationally activated by miR-24. REG4 can interact with transmembrane CD44, G protein-coupled receptor 37, mannan and heparin on cancer cells. Its overexpression was observed in gastric, colorectal, pancreatic, gallbladder, ovarian and urothelial cancers, and is closely linked to their aggressive behaviors and a poor prognosis. Additionally, REG4 expression and recombinant REG4 aggravated such cellular phenotypes as tumorigenesis, proliferation, anti-apoptosis, chemoradioresistance, migration, invasion, peritoneal dissemination, tumor growth, and cancer stemness via EGFR/Akt/activator protein-1 and Akt/glycogen synthase kinase three β/β-catenin/transcription factor 4 pathways. Sorted REG4-positive deep crypt secretory cells promote organoid formation of single Lgr5 (+) colon stem cells by Notch inhibition and Wnt activation. Histologically, REG4 protein is specifically expressed in neuroendocrine tumors and signet ring cell carcinomas of the gastrointestinal tract, pancreas, ovary, and lung. It might support the histogenesis of gastric intestinal-metaplasia-globoid dysplasia-signet ring cell carcinoma. In this review, we summarized the structure, biological functions, and effects of REG4 on inflammation and cancer. We conclude that REG4 may be employed as a biomarker of tumorigenesis, subsequent progression and poor prognosis of cancer, and may be a useful target for gene therapy.
Insights
Regenerating islet-derived 4 (REG4) is linked to inflammation and cancer. Overexpression of REG4 promotes tumor growth and poor prognosis, suggesting it as a potential biomarker and gene therapy target.
Area of Science:
- Molecular Biology
- Oncology
- Immunology
Background:
- Regenerating islet-derived 4 (REG4) is implicated in inflammation and tumorigenesis.
- REG4 influences macrophage polarization and bacterial clearance, and its expression is tightly regulated.
Purpose of the Study:
- To review the structure, biological functions, and roles of REG4 in inflammation and cancer.
- To explore REG4's potential as a biomarker and therapeutic target.
Main Methods:
- Literature review of studies on REG4's role in ulcerative colitis, cancer, and cellular pathways.
- Analysis of REG4 expression in various cancers and its correlation with prognosis.
Main Results:
- REG4 overexpression is observed in multiple cancers (gastric, colorectal, pancreatic, etc.) and linked to aggressive behaviors and poor prognosis.
- REG4 promotes tumorigenesis, proliferation, anti-apoptosis, migration, invasion, and cancer stemness via EGFR/Akt and Akt/GSK3β/β-catenin pathways.
- REG4 is specifically expressed in neuroendocrine tumors and signet ring cell carcinomas, potentially supporting histogenesis.
Conclusions:
- REG4 is a significant factor in cancer progression and prognosis.
- REG4 may serve as a valuable biomarker for tumorigenesis and cancer progression.
- REG4 presents a potential target for novel gene therapies in oncology.
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