title: Inhibition of c-Myc by let-7b mimic reverses mutidrug resistance in gastric cancer cells.
abstract: Chemotherapy is one of the few effective choices for patients with advanced or recurrent gastric cancer (GC). However, the development of mutidrug resistance (MDR) to cancer chemotherapy is a major obstacle to the effective treatment of advanced GC. Additionally, the mechanism of MDR remains to be determined. In the present study, we tested IC50 of cisplatin (DDP), vincristine (VCR) and 5-fluorouracil (5-FU) in SGC7901, SGC7901/DDP and SGC7901/VCR gastric cancer cells using an MTT assay. The expression of let-7b and c-Myc in these cells was detected by qPCR and western blot analysis. The relationship between let-7b and c-Myc was explored using a luciferase reporter assay. Transfection of let-7b mimic or inhibitor was used to confirm the effect of let-7b on drug sensitivity in chemotherapy via the regulation of c-Myc expression. We found that the expression of let-7b was lower in chemotherapy-resistant SGC7901/DDP and SGC7901/VCR gastric cancer cells than that in chemotherapy-sensitive SGC7901 cells. By contrast, the expression of c-Myc was higher in SGC7901/DDP and SGC7901/VCR cells than that in SGC7901 cells. Furthermore, we confirmed that let-7b suppresses c-Myc gene expression at the mRNA and protein levels in a sequence-specific manner, while transfection of let-7b mimic increases drug sensitivity in chemotherapy-resistant SGC7901/DDP and SGC7901/VCR cells by targeting downregulation of c-Myc. In SGC7901 drug-sensitive cells, however, the sensitivity of chemotherapy was significantly decreased following let-7b inhibitor transfection. The present study results demonstrated that let-7b increases drug sensitivity in chemotherapy‑resistant SGC7901/DDP and SGC7901/VCR gastric cancer cells by targeting the downregulation of c-Myc and that, let-7b mimic reverses MDR by promoting cancer stem cell differentiation controlled by double-negative autoregulatory loops (Lin28/let-7 and Myc/let-7) and a double-positive autoregulatory loop (Lin28/Lin28B/Myc) existing in GC cells, which remains to be confirmed.
authors: Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China.
authors: Xiaojun
authors: X
authors: Yang
authors: Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China.
authors: Hui
authors: H
authors: Cai
authors: Department of General Surgery, the People's Hospital of Baoji City, Baoji, Shaanxi 721000, P.R. China.
authors: Yuhe
authors: Y
authors: Liang
authors: Department of Infectious Disease, the First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
authors: Lin
authors: L
authors: Chen
authors: Department of General Surgery, the People's Hospital of Baoji City, Baoji, Shaanxi 721000, P.R. China.
authors: Xiangdong
authors: X
authors: Wang
authors: Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China.
authors: Ruohuang
authors: R
authors: Si
authors: Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China.
authors: Kunpeng
authors: K
authors: Qu
authors: Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China.
authors: Zebin
authors: Z
authors: Jiang
authors: Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China.
authors: Bingqiang
authors: B
authors: Ma
authors: Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China.
authors: Changfeng
authors: C
authors: Miao
authors: Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China.
authors: Jing
authors: J
authors: Li
authors: Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China.
authors: Bin
authors: B
authors: Wang
authors: Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China.
authors: Peng
authors: P
authors: Gao
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D025461:Feedback, Physiological; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016259:Genes, myc; D006801:Humans; D020128:Inhibitory Concentration 50; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000502:physiology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D014162:Transfection; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020413:3' Untranslated Regions; C489427:MYC protein, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C487931:mirnlet7 microRNA, human; D014750:Vincristine; D002945:Cisplatin; D005472:Fluorouracil