CARMA3 Promotes Colorectal Cancer Cell Motility and Cancer Stemness via YAP-Mediated NF-κB Activation

Abstract

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.

CARMA3: A potential therapeutic target in non-cancer diseases

“…Moreover, CARMA3 promotes cell invasion and migration, and is positively correlated with lung cancer stemness, metastasis, and poor survival outcomes ( 54 ). Similar results have been observed in hepatocellular carcinoma ( 56 ), colorectal cancer ( 57 , 58 ), ovarian cancer ( 59 ), breast cancer ( 60 , 61 ), and renal cell carcinoma ( 62 – 64 ). In conclusion, CARMA3 is involved in the development and pathogenesis of various types of cancers.…”

“…CARMA3, an oncoprotein overexpressed in various cancers, participates in cancer cell proliferation, migration, invasion, and apoptosis; it is related to the tumor node metastasis (TNM) stage, tumor status and grade, metastasis, and poor prognosis (51)(52)(53)(54)(55)(56)(57)(58)(59). CARMA3 has similar function in various cancers.…”

ANGPTL1 attenuates cancer migration, invasion, and stemness through regulating FOXO3a-mediated SOX2 expression in colorectal cancer

“…Migration and invasion abilities were assessed as previously described [ 20 ]. Briefly, cells were plated inside the upper chamber in medium without serum, and the lower chamber contained medium with 10% FBS as a chemoattractant at a 24-well plate.…”

“…Sphere formation was determined as previously described [ 20 ]. Cells were seeded on the ultra–low attachment 24-well plates (Corning Costar) with sphere formation medium, which was contained serum free culture medium, B27 supplement, recombinant human EGF (20 ng/ml), and basic FGF (10 ng/ml) for 14 days.…”

Editorial: Tumor Microenvironment and Cancer Cell Interactions in Solid Tumor Growth and Therapy Resistance

“…It is worth mentioning that an aberrant expression or activity of NF-κB family member proteins is a common hallmark of various cancers. The NF-κB proteins are a family of transcription factors that regulate the expression of a huge amount of genes and modulate a wide range of cellular processes affecting carcinogenesis, including protein synthesis (Fiume et al, 2013;Pisano et al, 2015), viral expression (Puca et al, 2007;Vitagliano et al, 2011), immune cell development (Fiume et al, 2013;Albano et al, 2019), inflammation (Taniguchi and Karin, 2018), apoptosis (Albensi) and cell survival (Luo et al, 2005), autophagy (Trocoli and Djavaheri-Mergny, 2011), cell motility (Chang et al, 2021). In particular, they found that FKBP51 depletion caused an increased expression of TNFrelated apoptosis-inducing ligand (TRAIL)-R2 (DR5), inducing a sensitization of melanoma cells to TRAIL-dependent apoptosis.…”