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.
Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
Dan
D
Liu
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Lei
L
Du
Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
Dong
D
Chen
Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Zhongde
Z
Ye
Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Hongxia
H
Duan
Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Tao
T
Tu
Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Jing
J
Feng
Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
Yili
Y
Yang
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Quan
Q
Chen
Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Xiyun
X
Yan
D021581:Active Transport, Cell Nucleus; D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D051929:CD146 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D060449:Wnt Signaling Pathway
D014408:Biomarkers, Tumor; D051929:CD146 Antigen; C497902:MCAM protein, human; D034741:RNA, Small Interfering; D038362:Glycogen Synthase Kinase 3
CD146; Wnt/β-catenin; colorectal cancer; stemness; tumorigenesis