Nodal promotes the self-renewal of human colon cancer stem cells via an autocrine manner through Smad2/3 signaling pathway.
Colorectal cancer is one of the most common and fatal tumors. However, molecular mechanisms underlying carcinogenesis of colorectal cancer remain largely undefined. Here, we explored the expression and function of Nodal in colon cancer stem cells (CCSCs). Nodal and its receptors were present in numerous human colorectal cancer cell lines. NODAL and ALK-4 were coexpressed in human colon cancerous tissues, and NODAL, CD24, and CD44, markers for CCSCs, were expressed at higher levels in human colon cancerous tissues than adjacent noncancerous colon tissues. Human CCSCs were isolated by magnetic activated cell sorting using anti-CD24 and anti-CD44. Nodal transcript and protein were hardly detectable in CD44- or CD24-negative human colorectal cancer cell lines, whereas Nodal and its receptors were present in CCSCs. Notably, Nodal facilitated spheroid formation of human CCSCs, and phosphorylation of Smad2 and Smad3 was activated by Nodal in cells of spheres derived from human CCSCs. Collectively, these results suggest that Nodal promotes the self-renewal of human CCSCs and mediate carcinogenesis of human colorectal cancer via an autocrine manner through Smad2/3 pathway. This study provides a novel insight into molecular mechanisms controlling fate of human CCSCs and offers new targets for gene therapy of human colorectal cancer.
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, China.
Yuehua
0000-0002-2910-7528
Y
Gong
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, China.
Ying
Y
Guo
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, China.
Yanan
Y
Hai
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, China.
Hao
H
Yang
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, China.
Yang
Y
Liu
Department of Urology, Shanghai Human Sperm Bank, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145 Shandong, Shanghai 200001, China.
Shi
S
Yang
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, China.
Zhenzhen
Z
Zhang
Department of Urology, Shanghai Human Sperm Bank, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145 Shandong, Shanghai 200001, China.
Meng
M
Ma
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, China.
Linhong
L
Liu
Department of Urology, Shanghai Human Sperm Bank, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145 Shandong, Shanghai 200001, China.
Zheng
Z
Li
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, China ; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200001, China ; Shanghai Key Laboratory of Reproductive Medicine, Shanghai 200025, China.
Zuping
Z
He
D019898:Autocrine Communication; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008024:Ligands; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D055457:Nodal Protein / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology
D051927:CD24 Antigen; D018960:Hyaluronan Receptors; D008024:Ligands; D055457:Nodal Protein; D012333:RNA, Messenger; D051899:Smad2 Protein; D051900:Smad3 Protein