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Downregulation of CLCA4 expression is associated with the development and progression of colorectal cancer.

ABSTRACT: The molecular mechanisms involved in the development and progression of colorectal cancer (CRC) are not completely understood. The present study aimed to identify potential novel genes involved in the development and progression of CRC. Database analysis revealed that the mRNA level of the chloride channel accessory 4 (CLCA4) was frequently lower in primary tumor tissues compared with that in corresponding non-cancerous colon tissues, and was even lower in liver metastases than in primary tumors. Further analyses through The Human Protein Atlas (THPA) website and immunohistochemistry (IHC)-based tissue microarray (TMA) confirmed that CLCA4 mRNA and protein expression were downregulated in CRC tissues. Furthermore, IHC-based TMA analysis revealed a gradual decrease in CLCA4 protein expression among colorectal normal, adenoma and carcinoma tissues. Survival analysis revealed that the decrease in CLCA4 mRNA expression was associated with the overall survival rate of patients with different types of tumor, including CRC, breast cancer, head and neck cancer and stomach cancer. Overall, downregulated CLCA4 expression may influence the development and progression of CRC.

SUBMITTER: Wei L

PROVIDER: S-EPMC7285744 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Downregulation of CLCA4 expression is associated with the development and progression of colorectal cancer.

Wei Lihui L Chen Wujin W Zhao Jinyan J Fang Yi Y Lin Jiumao J

Oncology letters 20200518 1

The molecular mechanisms involved in the development and progression of colorectal cancer (CRC) are not completely understood. The present study aimed to identify potential novel genes involved in the development and progression of CRC. Database analysis revealed that the mRNA level of the chloride channel accessory 4 (CLCA4) was frequently lower in primary tumor tissues compared with that in corresponding non-cancerous colon tissues, and was even lower in liver metastases than in primary tumors ...[more]

PMID: 32565987

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Project description:BackgroundEmerging evidence reveals that the initiation and development of human cancers, including colorectal cancer (CRC), are associated with the deregulation of circular RNAs (circRNAs). Our study intended to disclose the role of circ_0026416 in the malignant behaviors of CRC.MethodsThe detection for circ_0026416 expression, miR-545-3p expression, and myosin VI (MYO6) mRNA expression was performed using quantitative real-time PCR (qPCR). CCK-8 assay, colony formation assay, transwell assay, and flow cytometry assay were applied for functional analysis to monitor cell proliferation, migration, invasion, and apoptosis. The protein levels of MYO6 and epithelial mesenchymal-transition (EMT) markers were detected by western blot. Mouse models were used to determine the role of circ_0026416 in vivo. The potential relationship between miR-545-3p and circ_0026416 or MYO6 was verified by dual-luciferase reporter assay and RIP assay.ResultsThe expression of circ_0026416 was increased in CRC tumor tissues and cell lines. Circ_0026416 downregulation inhibited CRC cell proliferation, colony formation, migration, invasion, and EMT but induced cell apoptosis in vitro, and circ_0026416 knockdown also blocked tumor growth in vivo. MiR-545-3p was a target of circ_0026416, and rescue experiments indicated that circ_0026416 knockdown blocked CRC development by enriching miR-545-3p. In addition, miR-545-3p targeted MYO6 and inhibited MYO6 expression. MiR-545-3p enrichment suppressed CRC cell malignant behaviors by sequestering MYO6. Importantly, circ_0026416 knockdown depleted MYO6 expression by enriching miR-545-3p.ConclusionCirc_0026416 downregulation blocked the development of CRC through depleting MYO6 expression by enriching miR-545-3p.Highlights1. Circ_0026416 downregulation inhibits CRC development in vitro and in vivo. 2. Circ_0026416 regulates the expression of MYO6 by targeting miR-545-3p. 3. Circ_0026416 governs the miR-545-3p/MYO6 axis to regulate CRC progression.

Project description:BackgroundThe enrichment of peri-cancerous adipose tissue is a distinctive feature of colorectal cancer (CRC), accelerating disease progression and worsening prognosis. The communication between tumor cells and adjacent adipocytes plays a crucial role in CRC advancement. However, the precise regulatory mechanisms are largely unknown. This study aims to explore the mechanism of migration and invasion inhibitory protein (MIIP) downregulation in the remodeling of tumor cell-adipocyte communication and its role in promoting CRC.ResultsMIIP expression was found to be decreased in CRC tissues and closely associated with adjacent adipocyte browning. In an in vitro co-culture model, adipocytes treated with MIIP-downregulated tumor supernatant exhibited aggravated browning and lipolysis. This finding was further confirmed in subcutaneously allografted mice co-injected with adipocytes and MIIP-downregulated murine CRC cells. Mechanistically, MIIP interacted with the critical lipid mobilization factor AZGP1 and regulated AZGP1's glycosylation status by interfering with its association with STT3A. MIIP downregulation promoted N-glycosylation and over-secretion of AZGP1 in tumor cells. Subsequently, AZGP1 induced adipocyte browning and lipolysis through the cAMP-PKA pathway, releasing free fatty acids (FFAs) into the microenvironment. These FFAs served as the primary energy source, promoting CRC cell proliferation, invasion, and apoptosis resistance, accompanied by metabolic reprogramming. In a tumor-bearing mouse model, inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, significantly improved therapeutic efficacy in CRC with abnormal MIIP expression.ConclusionsOur data demonstrate that MIIP plays a regulatory role in the communication between CRC and neighboring adipose tissue by regulating AZGP1 N-glycosylation and secretion. MIIP reduction leads to AZGP1 oversecretion, resulting in adipose browning-induced CRC rapid progression and poor prognosis. Inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, may represent a promising therapeutic strategy for CRC with aberrant MIIP expression.

Dataset Information

Downregulation of CLCA4 expression is associated with the development and progression of colorectal cancer.

Publications

Downregulation of CLCA4 expression is associated with the development and progression of colorectal cancer.

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