Reduced CD146 expression promotes tumorigenesis and cancer stemness in colorectal cancer through activating Wnt/β-catenin signaling
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Dan Liu1,5, Lei Du2, Dong Chen3, Zhongde Ye1, Hongxia Duan1, Tao Tu1, Jing Feng1, Yili Yang4, Quan Chen2, Xiyun Yan1
1Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
2State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
3Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
4Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
5College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
Xiyun Yan, email: firstname.lastname@example.org
Keywords: stemness, CD146, tumorigenesis, Wnt/β-catenin, colorectal cancer
Received: September 09, 2015 Accepted: April 18, 2016 Published: June 09, 2016
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.
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