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Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expression.

ABSTRACT: Colorectal cancer (CRC) remains one of the most common malignancies worldwide and its mechanism is unclear. Polymeric immunoglobulin receptor (PIGR) which plays an important role in mucosal immunity is widely expressed in the mucosal epithelium and is dysregulated in different tumors. However, the role and underlying mechanisms of PIGR in CRC remain unclear. Here, we demonstrated that PIGR was hypermethylated and downregulated in our cohort (N = 272), and these features were associated with reduced overall survival in patients (HR_methylation 1.61, 95% CI [1.11-2.33]). These findings were validated by external TCGA and GEO data. Moreover, PIGR overexpression inhibits CRC cell malignant phenotypes in vitro and impedes CRC cells growth in male BALB/c nude mice. Mechanistically, PIGR physically associates with RE1 silencing transcription factor (REST) and blocks the transcription of laminin subunit beta 3 (LAMB3). Subsequently, the AKT-FOXO3/4 axis was suppressed by downregulated LAMB3. In the drug sensitive assay, PIGR-overexpressing cells were more sensitive to cisplatin and gemcitabine. Together, PIGR may serve as a powerful prognostic biomarker and putative tumor suppressor by suppressing the AKT-FOXO3/4 axis by downregulating LAMB3 in CRC. Our study may offer a novel therapeutic strategy for treating CRC patients who highly express PIGR with cisplatin and gemcitabine.

SUBMITTER: Zhang D

PROVIDER: S-EPMC9389318 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expression.

Zhang Ding D Huang Hao H Zheng Ting T Zhang Lei L Cui Binbin B Liu Yanlong Y Tan Shiheng S Zhao Liyuan L Tian Tian T Gao Lijing L Fu Qingzhen Q Cheng Zesong Z Zhao Yashuang Y

Frontiers in oncology 20220805

Colorectal cancer (CRC) remains one of the most common malignancies worldwide and its mechanism is unclear. Polymeric immunoglobulin receptor (PIGR) which plays an important role in mucosal immunity is widely expressed in the mucosal epithelium and is dysregulated in different tumors. However, the role and underlying mechanisms of PIGR in CRC remain unclear. Here, we demonstrated that PIGR was hypermethylated and downregulated in our cohort (N = 272), and these features were associated with redu ...[more]

PMID: 35992840

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Project description:AIM: High mobility group box protein 1 (HMGB1) and receptor for the advanced glycation end product (RAGE) play pivotal roles in vascular inflammation and atherosclerosis. The aim of this study was to determine whether the HMGB1-RAGE axis was involved in the actions of simvastatin on vascular inflammation and atherosclerosis in ApoE(-/-) mice. METHODS: Five-week old ApoE(-/-) mice and wild-type C57BL/6 mice were fed a Western diet. At 8 weeks of age, ApoE(-/-) mice were administered simvastatin (50 mg·kg(-1)·d(-1)) or vehicle by gavage, and the wild-type mice were treated with vehicle. The mice were sacrificed at 11 weeks of age, and the atherosclerotic lesions in aortic sinus were assessed with Oil Red O staining. Macrophage migration was determined with scanning EM and immunohistochemistry. Human umbilical vein endothelial cells (HUVECs) were used for in vitro study. Western blots were used to quantify the protein expression of HMGB1, RAGE, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). RESULTS: Vehicle-treated ApoE(-/-) mice exhibited significant increases in aortic inflammation and atherosclerosis as well as enhanced expression of HMGB1, RAGE, VCAM-1, and MCP-1 in aortic tissues as compared to the wild-type mice. Furthermore, serum total cholesterol, triglyceride and LDL levels were markedly increased, while serum HDL level was decreased in vehicle-treated ApoE(-/-) mice. Administration with simvastatin in ApoE(-/-) mice markedly attenuated the vascular inflammation and atherosclerotic lesion area, and decreased the aortic expression of HMGB1, RAGE, VCAM-1, and MCP-1. However, simvastatin did not affect the abnormal levels of serum total cholesterol, triglyceride, LDL and HDL in ApoE(-/-) mice. Exposure of HUVECs to HMGB1 (100 ng/mL) markedly increased the expression of HMGB1, RAGE and VCAM-1, whereas pretreatment of the cells with simvastatin (10 μmol/L) blocked the HMGB1-caused changes. CONCLUSION: Simvastatin inhibits vascular inflammation and atherosclerosis in ApoE(-/-) mice, which may be mediated through downregulation of the HMGB1-RAGE axis.

Dataset Information

Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expression.

Publications

Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expression.

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