MiR-34a targets GAS1 to promote cell proliferation and inhibit apoptosis in papillary thyroid carcinoma via PI3K/Akt/Bad pathway

Ma, Yuju; Qin, Huadong; Cui, Yunfu

doi:10.1016/j.bbrc.2013.11.010

Cited by 99 publications

(78 citation statements)

References 31 publications

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“…27 To date, the overexpression of miR-34a has been described in both papillary tumors 12,17 and papillary thyroid carcinoma cell lines. 28 Recently, it has been suggested that its oncogenic effect in PTC involves activation of the PI3K/Akt/Bad pathway, 29 which is consistent with it having a master regulator role. Moreover, both miR-34a and -221 have been very recently identified in the TCGA data set as crucial regulators of the immune response activities among all papillary carcinoma variants studied by this consortium, 19 further confirming our results.…”

Section: Modern Pathology (2015) 28 748-757mentioning

confidence: 92%

MicroRNA deep-sequencing reveals master regulators of follicular and papillary thyroid tumors

et al. 2015

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MicroRNA deregulation could be a crucial event in thyroid carcinogenesis. However, current knowledge is based on studies that have used inherently biased methods. Thus, we aimed to define in an unbiased way a list of deregulated microRNAs in well-differentiated thyroid cancer in order to identify diagnostic and prognostic markers. We performed a microRNA deep-sequencing study using the largest well-differentiated thyroid tumor collection reported to date, comprising 127 molecularly characterized tumors with follicular or papillary patterns of growth and available clinical follow-up data, and 17 normal tissue samples. Furthermore, we integrated microRNA and gene expression data for the same tumors to propose targets for the novel molecules identified. Two main microRNA expression profiles were identified: one common for follicular-pattern tumors, and a second for papillary tumors. Follicular tumors showed a notable overexpression of several members of miR-515 family, and downregulation of the novel microRNA miR-1247. Among papillary tumors, top upregulated microRNAs were miR-146b and the miR-221~222 cluster, while miR-1179 was downregulated. BRAF-positive samples displayed extreme downregulation of miR-7 and -204. The identification of the predicted targets for the novel molecules gave insights into the proliferative potential of the transformed follicular cell. Finally, by integrating clinical follow-up information with microRNA expression, we propose a prediction model for disease relapse based on expression of two miRNAs (miR-192 and let-7a) and several other clinicopathological features. This comprehensive study complements the existing knowledge about deregulated microRNAs in the development of well-differentiated thyroid cancer and identifies novel markers associated with recurrence-free survival.

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Section: Modern Pathology (2015) 28 748-757mentioning

confidence: 92%

MicroRNA deep-sequencing reveals master regulators of follicular and papillary thyroid tumors

et al. 2015

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“…The PI3K/AKT signaling pathway is an intracellular signaling pathway important in regulating cell proliferation, cell cycle, apoptosis and differentiation (26)(27)(28). PI3K activation leads to phosphorylation and activation of the serine/threonine kinase AKT (29); therefore, AKT phosphorylation may be used to assess the activity of the PI3K/AKT signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Inï¿½vitro study on the role of SOX9 in trastuzumab resistance of adenocarcinoma of the esophagogastric junction

et al. 2018

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Abstract. Trastuzumab is recommended for the treatment of human epidermal growth factor receptor 2-positive adenocarcinoma of the esophagogastric junction (AEG) in combination with chemotherapy; however, drug resistance has severely affected its clinical application. The present study aimed to investigate the effect of sex determining region Y-box 9 (SOX9), a prognostic marker in adjuvant oncological settings, on AEG cell proliferation and apoptosis in the presence or absence of trastuzumab. Furthermore, the molecular mechanism underlying the role of SOX9 in trastuzumab resistance was explored. ESO26 cells were treated with various concentrations of trastuzumab, and trastuzumab induced SOX9 expression in a concentration-dependent manner, as determined by reverse transcription-quantitative polymerase chain reaction and western blotting analyses. Transfection of ESO26 cells with SOX9 small interfering RNA was conducted to knock down SOX9 expression, and the results of MTT and flow cytome try assays demonstrated that SOX9 knockdown sensitized ESO26 cells to trastuzumab by inhibiting cell proliferation and enhancing cell apoptosis. In addition, it was observed that the trastuzumab-induced phosphorylation of AKT was suppressed by SOX9 knockdown. In conclusion, the present study demonstrated that SOX9 participated in trastuzumab resistance by affecting cell proliferation and apoptosis, and indicated that SOX9 may exert its effect on trastuzumab resistance via activation of the phosphatidylinositol-3-kinase/AKT signaling pathway. This study identified a novel mechanism underlying trastuzumab resistance in vitro and may be useful in improving the efficacy of trastuzumab treatment. IntroductionAdenocarcinoma of the esophagogastric junction (AEG) is a lethal malignancy originating from the distal esophagus and the esophagogastric junction (1,2). The incidence of AEG has increased rapidly worldwide during the past two decades (3-6). The prognosis of AEG is poor due to distant metastasis at the time of diagnosis and the limited treatment options (7,8). Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), has emerged as an effective therapeutic option for AEG when combined with chemotherapy (9).In a phase III, open-label, international, randomized controlled trial, Bang et al (9) observed that patients treated with trastuzumab plus chemotherapy had longer median follow-up and median overall survival times compared with patients treated with chemotherapy alone. The authors suggested that trastuzumab in combination with chemotherapy may be a new standard option for the first-line treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer (9). International National Comprehensive Cancer Network Guidelines recommend the detection of HER2 in patients with AEG in order to guide the selection of further clinical treatment options (10). However, trastuzumab treatment is invalid for nearly half of HER2-positive patients (9), and the mechanisms of drug resistance are curre...

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“…More interestingly, a recent study reveals that miR-34a and miR-199a/b could inhibit AXL expression in solid tumors via epigenetic mechanisms (Mudduluru et al 2011); the importance of this observation is further strengthened by several studies reporting the close relationships between AXL and miR-34a in colon carcinoma (Kaller et al 2011), lung cancer (Lee et al 2011), breast cancer (Mackiewicz et al 2011, and leukemia (Boysen et al 2014). However, recent studies also show that miR-34a is highly expressed in papillary thyroid carcinoma (PTC) and functions as an oncogenic miRNA by regulating GAS1 expression via the PI3K/ Akt/Bad pathway to promote cell proliferation and prevent apoptosis (Cahill et al 2006;Ma et al 2013). Additionally, expression of miR-34a may also commonly be high in many human cancers (Dutta et al 2007).…”

Section: Regulation Of Axl Is Of Great Clinical Interest Because Of Amentioning

confidence: 98%

Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells

Cho

Huang

Shiah

et al. 2015

RNA

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The AXL receptor tyrosine kinase is frequently overexpressed in cancers and is important in cancer invasion/metastasis and chemoresistance. Here, we demonstrate a regulatory feedback loop between AXL and microRNA (miRNA) at the posttranscriptional level. Both the GAS6-binding domain and the kinase domain of AXL, particularly the Y779 tyrosine phosphorylation site, are shown to be crucial for this autoregulation. To clarify the role of miRNAs in this regulation loop, approaches using bioinformatics and molecular techniques were applied, revealing that miR-34a may target the 3 ′ UTR of AXL mRNA to inhibit AXL expression. Interestingly and importantly, AXL overexpression may induce miR-34a expression by activating the transcription factor ELK1 via the JNK signaling pathway. In addition, ectopic overexpression of ELK1 promotes apoptosis through, in part, down-regulation of AXL. Therefore, we propose that AXL is autoregulated by miR-34a in a feedback loop; this may provide a novel opportunity for developing AXL-targeted anticancer therapies.

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MiR-34a targets GAS1 to promote cell proliferation and inhibit apoptosis in papillary thyroid carcinoma via PI3K/Akt/Bad pathway

Cited by 99 publications

References 31 publications

MicroRNA deep-sequencing reveals master regulators of follicular and papillary thyroid tumors

MicroRNA deep-sequencing reveals master regulators of follicular and papillary thyroid tumors

Inï¿½vitro study on the role of SOX9 in trastuzumab resistance of adenocarcinoma of the esophagogastric junction

Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells

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