Abstract
To detect the expressions of microRNA-218 (miR-218) in an imatinib mesylate-sensitive human gastrointestinal stromal tumor (GIST) cells (GIST882) and an imatinib mesylate-resistant cell line (GIST430) and explore the roles of miR-218 and GIST cells in the sensitivity of gastrointestinal stromal tumor to imatinib mesylate and its potential signaling pathways, with an attempt to provide new insights for the treatment of GIST. The GIST cell lines (GIST882 and GIST430) were cultured in vitro. Quantitative real-time PCR (qRT-PCR) was utilized to determine the expression profiles of miR-218 in both GIST cell lines. Forty-eight hours after the transfection of the miR-218 mimic or miR-218 inhibitor in the GIST cells, the changes in the expression of miR-218 in the GIST cells were detected with qRT-PCR. The effects of the ectopic expression of miR-218 in GIST882 or GIST430 cells on the imatinib mesylate-induced GIST cell viability were determined by MTT. The effects of miR-218 ectopic expression on the apoptosis of imatinib mesylate-induce GIST cells were determined by Annexin V/PI double staining method and flow cytometry. The effects of miR-218 ectopic expression on the AKT and phospho-AKT (p-AKT) expressions of imatinib mesylate-induce GIST cells were determined by Western blot and flow cytometry with the PI3K pathway inhibitor Wortmannin. As shown by qRT-PCR, compared with that in the imatinib mesylate-sensitive GIST882, the expression of miR-218 in imatinib mesylate-resistant GIST430 was significantly decreased (P < 0.01). Compared with the control group, the expression of miR-218 significantly increased in the GIST882 48 h after the transfection of miR-218 mimic (P < 0.01) and significantly declined after the transfection of miR-218 inhibitor (P < 0.01). As shown by MTT and flow cytometry, after the expression of miR-218 was inhibited in GIST882 under the effect of imatinib mesylate, the cell viability significantly increased (P < 0.01) and the number of apoptotic cells significantly decreased (P < 0.05); on the contrary, the over-expression of miR-218 in GIST430 under the effect of imatinib mesylate resulted in the significantly decreased cell viability (P < 0.01) and the significantly increased number of apoptotic cells (P < 0.05). Western blot and flow cytometry showed that, in comparison to the control group, Wortmannin could significantly inhibit the expression of p-AKT in GIST430 cells (P < 0.01) and stimulated apoptosis (P < 0.01). The expression of miR-218 is down-regulated in an imatinib mesylate-resistant GIST cell line (GIST430), whereas miR-218 over-expression can improve the sensitivity of GIST cells to imatinib mesylate, with PI3K/AKT signaling pathway possibly involved in the mechanism.
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References
Datar M, Khanna R (2012) Inpatient burden of gastrointestinal stromal tumors in the United States. J Gastrointest Oncol 3(4):335–341
Hodges K, Kennedy L, Meng F, Alpini G, Francis H (2012) Mast cells, disease and gastrointestinal cancer: a comprehensive review of recent findings. Transl Gastrointest Cancer 1(2):138–150
Halpern J, Kim YJ, Sultana R, Villani G (2012) Effectiveness of radiation therapy in GIST: a case report. J Gastrointest Oncol 3(2):143–146
McDaniel K, Correa R, Zhou T, Johnson C, Francis H, Glaser S, Venter J, Alpini G, Meng F (2013) Functional role of microvesicles in gastrointestinal malignancies. Ann Transl Med 1(1):4
Kanda T (2013) Criminal or bystander: imatinib and second primary malignancy in GIST patients. Chin J Cancer Res 25(5):490–492
Kinross KM, Sheppard KE, Pearson RB, Phillips WA (2012) Targeting cancer with PI3K pathway inhibitors: who to aim at? Transl Cancer Res 1(2):119–121
Sun X, Wang J, Yang G (2012) Surgical treatment of esophageal leiomyoma larger than 5 cm in diameter: a case report and review of the literature. J Thorac Dis 4(3):323–326
Zhao X, Yue C (2012) Gastrointestinal stromal tumor. J Gastrointest Oncol 3(3):189–208
Eisenberg BL, Pipas JM (2012) Gastrointestinal stromal tumor—background, pathology, treatment. Hematol Oncol Clin N Am 26(6):1239–1259
Kee D, Zalcberg JR (2012) Current and emerging strategies for the management of imatinib-refractory advanced gastrointestinal stromal tumors. Ther Adv Med Oncol 4(5):255–270
Nannini M, Biasco G, Astolfi A et al (2013) An overview on molecular biology of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST). J Med Genet 50(10):653–661
Wang C, Jin MS, Zou YB et al (2013) Diagnostic significance of DOG-1 and PKC-theta expression and c-Kit/PDGFRA mutations in gastrointestinal stromal tumours. Scand J Gastroenterol 48(9):1055–1065
O’Brien KM, Orlow I, Antonescu CR et al (2013) Gastrointestinal stromal tumors, somatic mutations and candidate genetic risk variants. PLoS One 8(4):e62119
Tan CJ, Yang JL, Crowe P, Goldstein D (2013) Targeted therapy in soft tissue sarcoma: a novel direction in therapeutics. Chin Clin Oncol 2(3):22
Rutkowski P, Bylina E, Klimczak A et al (2012) The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure-one institution study. BMC Cancer 12:107
Joensuu H (2013) Gastrointestinal stromal tumors: risk assessment and adjuvant therapy. Hematol Oncol Clin N Am 27(5):889–904
Tirumani SH, Jagannathan JP, Krajewski KM et al (2013) Imatinib and beyond in gastrointestinal stromal tumors: a radiologist’s perspective. AJR Am J Roentgenol 201(4):801–810
An HJ, Ryu MH, Ryoo BY et al (2013) The effects of surgical cytoreduction prior to imatinib therapy on the prognosis of patients with advanced GIST. Ann Surg Oncol 20(13):4212–4218
Fujimoto Y, Akiyoshi T, Konishi T et al (2013) Laparoscopic sphincter-preserving surgery (intersphincteric resection) after neoadjuvant imatinib treatment for gastrointestinal stromal tumor (GIST) of the rectum. Int J Colorectal Dis 29(1):111–116
Das D, Ganguly S, Deb AR et al (2013) Neoodjuvant imatinib mesylate for advanced primary and metastactic/recurrent gastro-intestinal stromal tumour (GIST). J Indian Med Assoc 111(1):21–23
Falor A, Arrington AK, Luu C et al (2013) Massive intra-abdominal imatinib-resistant gastrointestinal stromal tumor in a 21-year-old male. Case Rep Med 2013:373981
Linch M, Claus J, Benson C (2013) Update on imatinib for gastrointestinal stromal tumors: duration of treatment. Onco Targets Ther 6:1011–1023
Blay JY, Rutkowski P (2013) Adherence to imatinib therapy in patients with gastrointestinal stromal tumors. Cancer Treat Rev 40(2):242–247
Wang Q, Wei L, Guan X et al (2013) Briefing in family characteristics of microRNAs and their applications in cancer research. Biochim Biophys Acta 1844(1 Pt B):191–197
Kaplan BB, Kar AN, Gioio AE et al (2013) MicroRNAs in the axon and presynaptic nerve terminal. Front Cell Neurosci 7:126
Li M, Fu W, Wo L et al (2013) miR-128 and its target genes in tumorigenesis and metastasis. Exp Cell Res 319(20):3059–3064
Leite-Moreira AM, Lourenco AP, Falcao-Pires I et al (2013) Pivotal role of microRNAs in cardiac physiology and heart failure. Drug Discov Today 18(23–24):1243–1249
Piva R, Spandidos DA, Gambari R (2013) From microRNA functions to microRNA therapeutics: novel targets and novel drugs in breast cancer research and treatment (Review). Int J Oncol 43(4):985–994
Shi Y, Wang CZ, Hou YY et al (2013) Screening of differentially expressed microRNAs in borderline and malignant gastrointestinal stromal tumors. Zhonghua Bing Li Xue Za Zhi 42(1):20–25
Tu Y, Gao X, Li G et al (2013) MicroRNA-218 inhibits glioma invasion, migration, proliferation and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. Cancer Res 73(19):6046–6055
Jin J, Cai L, Liu ZM et al (2013) miRNA-218 inhibits osteosarcoma cell migration and invasion by down-regulating of TIAM1, MMP2 and MMP9. Asian Pac J Cancer Prev 14(6):3681–3684
Li J, Ping Z, Ning H (2012) MiR-218 impairs tumor growth and increases chemo-sensitivity to cisplatin in cervical cancer. Int J Mol Sci 13(12):16053–16064
Tuveson DA, Willis NA, Jacks T et al (2001) STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 20(36):5054–5058
Reichardt P, Joensuu H, Blay JY (2013) New fronts in the adjuvant treatment of GIST. Cancer Chemother Pharmacol 72(4):715–723
Kwong LN, Davies MA (2013) Navigating the therapeutic complexity of PI3K pathway inhibition in melanoma. Clin Cancer Res 19(19):5310–5319
Kitagishi Y, Matsuda S (2013) Diets involved in PPAR and PI3K/AKT/PTEN pathway may contribute to neuroprotection in a traumatic brain injury. Alzheimers Res Ther 5(5):42
Siegfried Z, Bonomi S, Ghigna C et al (2013) Regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing in cancer. Int J Cell Biol 2013:568931
Blume-Jensen P, Jiang G, Hyman R et al (2000) Kit/stem cell factor receptor-induced activation of phosphatidylinositol 3′-kinase is essential for male fertility. Nat Genet 24(2):157–162
Gibbons SJ, Rich A, Distad MA et al (2003) Kit/stem cell factor receptor-induced phosphatidylinositol 3′-kinase signalling is not required for normal development and function of interstitial cells of Cajal in mouse gastrointestinal tract. Neurogastroenterol Motil 15(6):643–653
Rajendra R, Pollack SM, Jones RL (2013) Management of gastrointestinal stromal tumors. Future Oncol 9(2):193–206
Floris G, Wozniak A, Sciot R et al (2013) A potent combination of the novel PI3K inhibitor, GDC-0941, with imatinib in gastrointestinal stromal tumor xenografts: long-lasting responses after treatment withdrawal. Clin Cancer Res 19(3):620–630
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This study was supported by Key Project of Science and Technology Commission of Shanghai Municipality (No. 13411950900).
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Fan, R., Zhong, J., Zheng, S. et al. microRNA-218 increase the sensitivity of gastrointestinal stromal tumor to imatinib through PI3K/AKT pathway. Clin Exp Med 15, 137–144 (2015). https://doi.org/10.1007/s10238-014-0280-y
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DOI: https://doi.org/10.1007/s10238-014-0280-y