Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells.
Abnormalities in the STAT3 pathway are involved in the oncogenesis of several cancers. However, the mechanism by which dysregulated STAT3 signaling contributes to the progression of human colorectal cancer (CRC) has not been elucidated, nor has the role of JAK, the physiological activator of STAT3, been evaluated. To investigate the role of both JAK and STAT3 in CRC progression, we inhibited JAK with AG490 and depleted STAT3 with a SiRNA. Our results demonstrate that STAT3 and both JAK1 and 2 are involved in CRC cell growth, survival, invasion, and migration through regulation of gene expression, such as Bcl-2, p1(6ink4a), p21(waf1/cip1), p27(kip1), E-cadherin, VEGF, and MMPs. Importantly, the FAK is not required for STAT3-mediated regulation, but does function downstream of JAK. In addition, our data show that proteasome-mediated proteolysis promotes dephosphorylation of the JAK2, and consequently, negatively regulates STAT3 signaling in CRC. Moreover, immunohistochemical staining reveals that nuclear staining of phospho-STAT3 mostly presents in adenomas and adenocarcinomas, and a positive correlation is found between phospho-JAK2 immunoreactivity and the differentiation of colorectal adenocarcinomas. Therefore, our findings illustrate the biologic significance of JAK1, 2/STAT3 signaling in CRC progression and provide novel evidence that the JAK/STAT3 pathway may be a new potential target for therapy of CRC.
Xiong
Hua
H
Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine, Ren-Ji Hospital, Shanghai Institute of Digestive Disease, Shanghai, 200001, China.
Zhang
Zhi-Gang
ZG
Tian
Xiao-Qing
XQ
Sun
Dan-Feng
DF
Liang
Qin-Chuan
QC
Zhang
Yan-Jie
YJ
Lu
Rong
R
Chen
Ying-Xuan
YX
Fang
Jing-Yuan
JY
D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D053614:Janus Kinase 2 / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D015820:Cadherins; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; D042461:Vascular Endothelial Growth Factor A; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D051417:Focal Adhesion Kinase 1; D053613:Janus Kinase 1; D053614:Janus Kinase 2; C496050:PTK2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde