Reduced CD146 expression promotes tumorigenesis and cancer stemness in colorectal cancer through activating Wnt/β-catenin signaling.
Cancer stemness drives tumor progression and drug resistance, representing a challenge to cancer eradication. Compelling evidence indicates that cancer cells can reenter the stem cell state due to the reprogramming of self-renewal machinery. Here, we show that CD146 knockdown induces stem cell properties in colorectal cancer (CRC) cells through activating canonical Wnt signaling. shRNA-mediated CD146 knockdown in CRC cells facilitates tumor initiation in serial xenotransplantation experiments. Moreover, upon CD146 knockdown, CRC cells show elevated expression of specific cancer stem cell (CSC) markers, increased sphere and clone formation as well as drug resistance in vitro. Mechanistically, our findings provide evidence that CD146 expression negatively correlates with canonical Wnt/β-catenin activity in CRC cell lines and primary CRC specimens. Knockdown of CD146 results in inhibition of NF-κB/p65-initiated GSK-3β expression, subsequently promoting nuclear translocation and activation of β-catenin, and as a consequence restoring stem cell phenotypes in differentiated CRC cells. Together, our data strongly suggest that CD146 functions as a suppressor of tumorigenesis and cancer stemness in CRC through inactivating the canonical Wnt/β-catenin cascade. Our findings provide important insights into stem cell plasticity and the multifunctional role of CD146 in CRC progression.
['Liu|Dan|D|', 'Du|Lei|L|', 'Chen|Dong|D|', 'Ye|Zhongde|Z|', 'Duan|Hongxia|H|', 'Tu|Tao|T|', 'Feng|Jing|J|', 'Yang|Yili|Y|', 'Chen|Quan|Q|', 'Yan|Xiyun|X|']
D021581:Active Transport, Cell Nucleus D000328:Adult D000818:Animals D014408:Biomarkers, Tumor D051929:CD146 Antigen D045744:Cell Line, Tumor D015179:Colorectal Neoplasms D018450:Disease Progression D005260:Female D015972:Gene Expression Regulation, Neoplastic D038362:Glycogen Synthase Kinase 3 D006801:Humans D008297:Male D051379:Mice D016688:Mice, Inbred NOD D016513:Mice, SCID D008875:Middle Aged D009368:Neoplasm Transplantation D014411:Neoplastic Stem Cells D020411:Oligonucleotide Array Sequence Analysis D010641:Phenotype D034741:RNA, Small Interfering D060449:Wnt Signaling Pathway
CD146 tumorigenesis stemness colorectal cancer Wnt/β-catenin