title: MicroRNA-451 regulates AMPK/mTORC1 signaling and fascin1 expression in HT-29 colorectal cancer.
abstract: The earlier studies have shown that Fascin1 (FSCN1), the actin bundling protein, is over-expressed in colorectal cancers, and is associated with cancer cell progression. Here, we aimed to understand the molecular mechanisms regulating FSCN1 expression by focusing on mammalian target of rapamycin (mTOR) signaling and its regulator microRNA-451. We found that microRNA-451 was over-expressed in multiple colorectal cancer tissues, and its expression was correlated with mTOR complex 1 (mTORC1) activity and FSCN1 expression. In cultured colorectal cancer HT-29 cells, knockdown of FSCN1 by RNAi inhibited cell migration and proliferation. Activation of mTORC1 was required for FSCN1 expression, HT-29 cell migration and proliferation, as RAD001 and rapamycin, two mTORC1 inhibitors, suppressed FSCN1 expression, HT-29 cell migration and proliferation. Meanwhile, forced activation of AMP-activated protein kinase (AMPK), the negative regulator of mTORC1, by its activators or by the genetic mutation, inhibited mTORC1 activation, FSCN1 expression, cell migration and proliferation. In HT-29 cells, we found that over-expression of microRNA-451 inhibited AMPK activation, causing mTORC1 over-activation and FSCN1 up-regulation, cells were with high migration ability and proliferation rate. Significantly, these effects by microRNA-451 were largely inhibited by mTORC1 inhibitors or the AMPK activator AICAR. On the other hand, knockdown of miRNA-451 by the treatment of HT-29 cells with miRNA-451 antagomir inhibited mTORC1 activation and FSCN1 expression. The proliferation and migration of HT-29 cells after miRNA-45 knockdown were also inhibited. Our results suggested that the over-expressed microRNA-451 in colon cancer cells might inhibit AMPK to activate mTORC1, which mediates FSCN1 expression and cancer cell progression.
authors.affiliation: Department of Medical Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, 91 Qianjin Road, Kunshan 215300, Jiangsu Province, China.
authors.forename: Min-Bin
authors.initials: MB
authors.lastname: Chen
authors.forename: Mu-Xin
authors.initials: MX
authors.lastname: Wei
authors.forename: Jun-Yi
authors.initials: JY
authors.lastname: Han
authors.forename: Xiao-Yang
authors.initials: XY
authors.lastname: Wu
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.forename: Pei-Hua
authors.initials: PH
authors.lastname: Lu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D034622:RNA Interference / Q000187:drug effects; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C502658:FSCN1 protein, human; C531201:MIRN451 microRNA, human; D035683:MicroRNAs; D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside; ACC; AICAR; AMP-activated protein kinase; AMPK; Acetyl-CoA Carboxylase; CAB39; Colorectal cancer; FSCN1; Fascin1; MicroRNA; RNA interference; RNAi; Raptor; S6K1; TSC2; Tuberous sclerosis protein 2 and untranslated regions (UTRs); calcium-binding protein 39; fascin1, mammalian target of rapamycin (mTOR); mTOR complex 1; mTOR signaling; mTORC1; regulatory associated protein of mTOR; ribosomal p70 S6 kinase