Identification of miRNomes in human stomach and gastric carcinoma reveals miR-133b/a-3p as therapeutic target for gastric cancer.
Gastric cancer (GC) is the fourth most frequent malignant disease and the second leading cause of cancer mortality worldwide, but the molecular mechanisms underlying this clinically heterogeneous disease are complex and remain far from completely understood. Accumulating evidence suggests that abnormal microRNA (miRNA) expression is involved in tumorigenesis. However, their accurate expression pattern, function, and mechanism in GC remain unclear. Here, a heatmap analysis of the miRNomes was performed across TCGA datasets and the expression of miR-133 family was found to be consistently downregulated in GC. This result was confirmed in two GC cell lines and 20 pairs of primary GC tissues, and further study demonstrated that the downregulation of miR-133 was mainly mediated by histone modification within its promoter region. Importantly, restoration of miR-133b/a-3p expression could suppress GC cell proliferation and promote cell apoptosis by targeting anti-apoptotic molecules Mcl-1 and Bcl-xL. Consistent with in vitro results, reintroducing of miR-133b/a-3p expression significantly delayed tumor formation and reduced tumor size of GC cells in xenograft nude mice. And the inverse relationship between miR-133b/a-3p and its targets was verified in xenograft mice. Taken together, our findings suggest that miR-133b/a-3p acts as a tumor suppressor in GC by directly targeting Mcl-1 and Bcl-xL. Revealing novel mechanism for oncogene inhibition by miRNA-mediated pathways offers new avenues for GC treatment.
National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, China; Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Yanfang
Y
Liu
Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Xin
X
Zhang
Department of Rehabilitation Medicine, No. 309 Hospital of PLA, Beijing 100000, China.
Yujing
Y
Zhang
Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Zunqi
Z
Hu
Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Dejun
D
Yang
Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Changming
C
Wang
Department of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China. Electronic address: Guo918meng@163.com.
Meng
M
Guo
Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China. Electronic address: caiqp1969@hotmail.com.
Qingping
Q
Cai
D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D034622:RNA Interference; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D020413:3' Untranslated Regions; C494811:BCL2L1 protein, human; D006657:Histones; C579095:MCL1 protein, human; C548234:MIRN133 microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051020:bcl-X Protein
Apoptosis; Gastric cancer; Therapy; miRNomes; microRNA