title: Cullin 4A (CUL4A), a direct target of miR-9 and miR-137, promotes gastric cancer proliferation and invasion by regulating the Hippo signaling pathway.
abstract: Although Cullin 4A (CUL4A) is mutated or amplified in several human cancer types, its role in gastric cancer (GC) and the mechanisms underlying its regulation remain largely uncharacterized. In the present study, we report that the expression of CUL4A significantly correlated with the clinical stage of the tumor and lymph node metastasis, and survival rates were lower in GC patients with higher levels of CUL4A than in patients with lower CUL4A levels. The upregulation of CUL4A promoted GC cell proliferation and epithelial-mesenchymal transition (EMT) by downregulating LATS1-Hippo-YAP signaling. Knocking down CUL4A had the opposite effect in vitro and in vivo. Interestingly, CUL4A expression was inhibited by the microRNAs (miRNAs), miR-9 and miR-137, which directly targeted the 3'-UTR of CUL4A. Overexpression of miR-9 and miR-137 downregulated the CUL4A-LATS1-Hippo signaling pathway and suppressed GC cell proliferation and invasion in vitro. Taken together, our findings demonstrate that perturbations to miR-9/137-CUL4A-Hippo signaling contribute to gastric tumorigenesis, and suggest potential therapeutic targets for the future treatment of GC.
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Jun
authors: J
authors: Deng
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Wan
authors: W
authors: Lei
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Xiaojun
authors: X
authors: Xiang
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Ling
authors: L
authors: Zhang
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Jun
authors: J
authors: Lei
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Yu
authors: Y
authors: Gong
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Meijiao
authors: M
authors: Song
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Yi
authors: Y
authors: Wang
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Ziling
authors: Z
authors: Fang
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Feng
authors: F
authors: Yu
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Miao
authors: M
authors: Feng
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Ze
authors: Z
authors: Sun
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Jun
authors: J
authors: Chen
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Zhengyu
authors: Z
authors: Zhan
authors: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
authors: Jianping
authors: J
authors: Xiong
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D020413:3' Untranslated Regions; C114234:CUL4A protein, human; D044842:Cullin Proteins; C545567:MIRN137 microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases
keywords: CUL4A; Hippo; gastric cancer; miR-137; miR-9