Abstract
Simple SummaryCARMA3 is overexpressed in most cancers, and its expression is positively associated with poor prognosis. In this study, we evaluated the detailed mechanisms of CARMA3-mediated CRC metastasis. We found that overexpression of CARMA3 induced the expression of YAP and NF-κB activation, then elicited EMT induction to enhance cell migration and invasion. We demonstrate for the first time that YAP is a critical downstream regulator of CARMA3 in CRC. Our findings reveal a regulation axis between CARMA3 and Hippo oncoprotein YAP and further support the potential role of CARMA3 in the metastasis and cancer stemness of CRC.CARD-recruited membrane-associated protein 3 (CARMA3) is overexpressed in various cancers and is associated with cancer cell proliferation, metastasis, and tumor progression; however, the underlying mechanisms of CARMA3 in colorectal cancer (CRC) metastasis remain unclear. Here, we found that higher CARMA3 expression was correlated with poor overall survival and metastasis in CRC patients from the TNMplot database and Human Tissue Microarray staining. Elevating CARMA3 expression promoted cell proliferation, epithelial-mesenchymal transition (EMT) induction, migration/invasion abilities, sphere formation, and cancer stem cell markers expression. Knockdown of CARMA3 decreased these processes via the EMT-related transcription factor Slug. Moreover, CARMA3 depletion significantly reduced tumor growth in mice that were consistent with the in vitro results. CRC migration/invasion could be regulated by CARMA3/YAP/Slug signaling axis using genetic inhibition of Yes-associated protein (YAP). Interestingly, CARMA3 induced activation of nuclear factor (NF)-κB through YAP expression, contributing to upregulation of Slug. YAP expression positively correlated with CARMA3, NF-κB, and Slug gene expression and poor clinical outcomes in CRC patients. Our findings demonstrate for the first time that CARMA3 plays an important role in CRC progression, which may serve as a potential diagnostic biomarker and candidate therapeutic target for CRC treatment.
Highlights
Colorectal cancer (CRC) is the third commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide in 2020 [1]
We demonstrated a novel mechanism by which CARD-recruited membrane-associated protein 3 (CARMA3) induced Yes-associated protein (YAP) expression and subsequently enhanced nuclear factor (NF)-κB activation, epithelial-mesenchymal transition (EMT)-related transcription factor Slug expression, and metastasis
Using the paired colorectal cancer (CRC) and metastatic tissues in Tissue Microarray (TMA), we observed that higher levels of CARMA3 scores in metastatic tissues compared to non-metastatic CRC tissues (Figure 1E)
Summary
Colorectal cancer (CRC) is the third commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide in 2020 [1]. 20% of CRC patients are diagnosed with distant metastasis and the 5-year relative survival outcomes remain poor, with less than 20% [2]. It is essential to investigate genes and mechanisms involved in tumor metastasis, which can supply novel diagnostic biomarkers or therapeutic targets for CRC. CARMA3 has been shown to be overexpressed in various human cancers [3]. Several studies reported that inhibition of CARMA3 decreased cell proliferation, migration, and tumor growth in NSCLC, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, and colorectal cancer [4,5,6,7,8]. Previous studies have found that NF-κB activation drives cancer cell proliferation, metastasis, and angiogenesis in different cellular contexts [11,12]. The other possible molecular mechanisms of CARMA3 in CRC were largely unclear
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