Loss of Tumor Suppressor C9orf9 Promotes Metastasis in Colorectal Cancer
Erfei Chen1,2, Fangfang Yang1,2, Qiqi Li1,2
1Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi'an 710069, China.
Abstract:
The whole genome sequencing of tumor samples identifies thousands of somatic mutations. However, the function of these genes or mutations in regulating cancer progression remains unclear. We previously performed exome sequencing in patients with colorectal cancer, and identified one splicing mutation in C9orf9. The subsequent target sequencing of C9orf9 gene based on a validation cohort of 50 samples also found two function mutations, indicating that the loss of wild-type C9orf9 may participate in the tumorigenesis of colorectal cancer. In this research, we aimed to further confirm the function of C9orf9 in the CRC phenotype. Our Q-PCR analysis of the tumor and matched normal samples found that C9orf9 was downregulated in the CRC samples. Function assays revealed that C9orf9 exerts its tumor suppressor role mainly on cancer cell migration and invasion, and its loss was essential for certain tumor-microenvironment signals to induce EMT and metastasis in vivo. RNA-sequencing showed that stable-expressing C9orf9 can inhibit the expression of several metastasis-related genes and pathways, including vascular endothelial growth factor A (VEGFA), one of the essential endothelial cell mitogens which plays a critical role in normal physiological and tumor angiogenesis. Overall, our results showed that the loss of C9orf9 contributes to the malignant phenotype of CRC. C9orf9 may serve as a novel metastasis repressor for CRC.
Insights
Loss of C9orf9 gene expression promotes colorectal cancer (CRC) progression by increasing cell migration and invasion. C9orf9 acts as a tumor suppressor, potentially serving as a novel target for CRC metastasis treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Whole genome sequencing reveals numerous somatic mutations in tumors, but their functional roles in cancer progression are often unknown.
- Previous exome sequencing in colorectal cancer (CRC) identified mutations in the C9orf9 gene, suggesting its potential involvement in CRC tumorigenesis.
Purpose of the Study:
- To elucidate the functional role of C9orf9 in colorectal cancer (CRC) phenotype.
- To investigate C9orf9's involvement in cancer cell migration, invasion, and metastasis.
Main Methods:
- Quantitative Polymerase Chain Reaction (Q-PCR) to assess C9orf9 expression levels in CRC and normal tissues.
- Functional assays to evaluate the impact of C9orf9 on cancer cell migration and invasion.
- RNA sequencing to identify downstream targets and pathways affected by C9orf9 expression.
Main Results:
- C9orf9 expression was significantly downregulated in colorectal cancer (CRC) samples compared to matched normal tissues.
- Loss of C9orf9 function promoted cancer cell migration and invasion, facilitating tumor metastasis.
- Stable expression of C9orf9 inhibited metastasis-related genes and pathways, including vascular endothelial growth factor A (VEGFA).
Conclusions:
- The loss of C9orf9 contributes to the malignant phenotype of colorectal cancer (CRC), particularly promoting metastasis.
- C9orf9 functions as a tumor suppressor and may represent a novel therapeutic target for inhibiting CRC metastasis.
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