The miR-1269a/PCDHGA9/CXCR4/β-catenin pathway promotes colorectal cancer invasion and metastasis

被引：2

作者：

Mei, Haitao ^{[1
,2
,3
]}

Luo, Qingshan ^{[2
]}

Weng, Junyong ^{[3
,5
]}

Hao, Jialing ^{[2
]}

Cai, Jinfeng ^{[2
]}

Zhou, Runkai ^{[2
]}

Bian, Ce ^{[3
]}

Ye, Yingzi ^{[6
]}

Luo, Shengzheng ^{[4
]}

Wen, Yugang ^{[2
]}

机构：

[1] Shanghai Univ Tradit Chinese Med, Shanghai Municipal Hosp Tradit Chinese Med, Dept Gastrointestinal Surg, 274 Middle Zhijiang Rd, Shanghai 200071, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Gen Surg, 85 Wujin Rd, Shanghai 200080, Peoples R China

[3] Navy Med Univ, Changzheng Hosp, Dept Colorectal Surg, 415 Fengyang Rd, Shanghai 200003, Peoples R China

[4] Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Gastroenterol, 85 Wujin Rd, Shanghai 200080, Peoples R China

[5] Fudan Univ, Shanghai Canc Ctr, Dept Colorectal Surg, 270 Dong An Rd, Shanghai 200032, Peoples R China

[6] Fudan Univ, Childrens Hosp, Dept Infect Dis, 399 Wanyuan Rd, Shanghai 201102, Peoples R China

来源：

CELLULAR & MOLECULAR BIOLOGY LETTERS | 2024年 / 29卷 / 01期

基金：

中国国家自然科学基金;

关键词：

CRC; PCDHGA9; miR-1269a; HOXA1; CXCR4; beta-Catenin; EPITHELIAL-MESENCHYMAL TRANSITION; WNT/BETA-CATENIN PATHWAY; PROGRESSION; ACTIVATION; EMT;

D O I：

10.1186/s11658-024-00656-9

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

BackgroundColorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. This research focuses on investigating the impact and underlying molecular mechanisms of protocadherin gamma subfamily A, 9 (PCDHGA9) on the invasion and metastasis of CRC, aiming to identify more precise molecular markers for the diagnosis and prognosis of CRC.MethodsPCDHGA9 expression was detected using quantitative real-time quantitative polymerase chain reaction (RT-qPCR) in 63 pairs of colorectal cancer tissues. Differential gene expression from high-throughput sequencing was analyzed using ingenuity pathway analysis (IPA) to explore the biological functions of PCDHGA9 and its potential regulated genes. Bioinformatics tools were employed to explore potential upstream regulatory microRNAs of PCDHGA9. Dual-luciferase assays were performed to demonstrate the regulation between PCDHGA9 and miR-1269a. Protein mass spectrometry suggested an interaction between PCDHGA9 and HOXA1. JASPAR predicted that HOXA1 may act as a transcription factor of CXCR4. Coimmunoprecipitation, dual-luciferase assays, and nuclear-cytoplasmic fractionation experiments confirmed the molecular mechanism involving PCDHGA9, CXCR4, HOXA1, and beta-catenin. Transwell, wound healing, and western blot assays were conducted to confirm the impact of PCDHGA9, miR-1269a, and CXCR4 on the invasion, metastasis, and epithelial-mesenchymal transition (EMT) functions of CRC cells in in vitro experiments. A whole-body fluorescence imaging system was used to evaluate the combined impact of miR-1269a and PCDHGA9 on the invasion and metastasis of CRC in in vivo experiments.ResultsThe expression of PCDHGA9 was found to be lower in CRC tissues compared with their corresponding adjacent tissues. Low expression of PCDHGA9 potentially correlated with worse prognosis and increased chances of invasion and metastasis in CRC. miR-1269a was highly expressed in CRC tissues and acted as a negative regulator for PCDHGA9, promoting invasion, migration, and EMT of CRC cells. PCDHGA9's interaction with HOXA1 downregulated CXCR4, a transcription factor, leading to accumulation of beta-catenin and further promoting invasion, migration, and EMT of CRC cells.ConclusionsPCDHGA9, acting as a tumor suppressor, is downregulated by miR-1269a. The low level of PCDHGA9 activates the Wnt/beta-catenin pathway by releasing its interaction with HOXA1, promoting the expression of CXCR4, and causing invasion, migration, and EMT in CRC.

引用

页数：25