P53-dependent miRNAs mediate nitric oxide-induced apoptosis in colonic carcinogenesis.
Both miRNAs and nitric oxide (NO) play important roles in colonic inflammation and tumorigenesis. Resistance of colonic epithelial cells to apoptosis may contribute to tumor development. We hypothesized that some miRNAs could increase the resistance of colonic cancer cells to nitric oxide-induced apoptotic cell death. Here we show that NO induced apoptosis and stimulated expression of some miRNAs. Loss of p53 not only blocked NO-induced apoptosis but also dramatically inhibited the expression of NO-related miRNAs, such as miR-34, miR-203, and miR-1301. In addition, blockage of p53-dependent miRNAs significantly reduced NO-induced apoptosis. Furthermore, forced expression of these miRNAs rendered HT-29 cells, which are resistant to apoptosis with mutant p53, more sensitive to NO-induced apoptotic cell death. Most interestingly, in a colitis-associated colon cancer mouse model, the level of miRNAs dropped significantly, accompanied by downregulation of p21, which is a key target gene of p53. In human colorectal cancer samples, the expression of miR-34 significantly correlated with the level of inducible nitric oxide synthase (iNOS). We contend that increased NO production may select cells with low levels of p53-dependent miRNAs which contributes to human colonic carcinogenesis and tumor progression.
State Key Laboratory of Molecular Oncology, Peking Union Medical College, Beijing, China.
Weiwei
W
Li
State Key Laboratory of Molecular Oncology, Peking Union Medical College, Beijing, China.
Wenxiao
W
Han
State Key Laboratory of Molecular Oncology, Peking Union Medical College, Beijing, China.
Yiming
Y
Ma
Department of Gastrointestinal Cancer Surgery, Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Liang
L
Cui
Department of Gastrointestinal Cancer Surgery, Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Yantao
Y
Tian
Department of Gastrointestinal Cancer Surgery, Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Zhixiang
Z
Zhou
State Key Laboratory of Molecular Oncology, Peking Union Medical College, Beijing, China. Electronic address: hongyingwang@cicams.ac.cn.
Hongying
H
Wang
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
Apoptosis; Colon cancer; Inflammation; Nitric oxide; miRNA; p53