miR-200c inhibits TGF-β-induced-EMT to restore trastuzumab sensitivity by targeting ZEB1 and ZEB2 in gastric cancer

Zhou, Xin; Men, Xinyi; Zhao, Riyang; Han, Jing; Zhang, Fan; Wang, Yudong; Lv, Yalei; Zuo, Jian; Zhao, Lianmei; Sang, Meixiang; Liu, Xian De; Shan, Baoen

doi:10.1038/s41417-017-0005-y

Cited by 70 publications

(52 citation statements)

References 31 publications

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“…We confirmed the activatory role of miR-145, miR-200c, miR-205 on CDH1 expression in VRCs. We also confirmed that miR-200c expression decreased ZEB1 level in VRCs [53], but we did not observe any effect on miR-200c on ZEB2 expression [54]. VRCs overexpressed miR-205 shown ZEB1/2 downregulation in cancer cells, what is in accordance with previous works [55,56].…”

Section: Discussionsupporting

confidence: 92%

Genetical engineered lung cancer cell for analyzing Epithelial-Mesenchymal transition

Kiełbus

Czapiński

Kałafut

et al. 2019

Preprint

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Cell plasticity, defined as the ability to undergo phenotypical transformation in a reversible 12 manner, is a physiological processes that also exert important roles in disease progression Two forms 13 of cellular plasticity are epithelial-mesenchymal transition (EMT) and its inverse process, 14 mesenchymal-epithelial transition (MET). These processes have been correlated to the poor outcome 15 of different types of neoplasias as well as drug resistance development. Since EMT/MET are 16 transitional processes, we have generated and validated a reporter cell line. Specifically, a far-red 17 fluorescent protein was knocked-in in-frame with the mesenchymal gene marker VIMENTIN (VIM) 18 in H2170 lung cancer cells. The vimentin reporter cells (VRCs) are a reliable model for studying EMT 19 and MET showing cellular plasticity upon a series of stimulations. These cells are a robust platform 20 to dissect the molecular mechanisms of these processes, and for drug discovery in vitro and in the 21 future in vivo.22 Keywords: epithelial-mesenchymal transition (EMT); mesenchymal-epithelial transition (MET); 23 cancer cell line; vimentin; reporter; 24 25 29 transition (EMT) and mesenchymal-epithelial transition (MET), respectively. EMT has been 30 correlated to the metastasis and invasion potential of many types of malignancies [2]. The fact that 31 the poor outcome of many types of neoplasias correlates with EMT/MET, makes these molecular 32 phenomena important focus for research and drug targeting [3-6]. Despite the clinical association,33 the role of EMT/MET in metastasis is inconclusive, for example mesenchymal-like prostate cancer 34 cells survive in circulation but, unlike epithelial or cells undergoing EMT, they are unable to form 35 macrometastases [7]. In fact, breast cancer cell metastasis to lung tissue in mice was not affected by36 decreasing EMT -by targeting EMT-triggering transcription factors such as SNAI1 (Snail) and SNAI2 37 (Slug) by overexpressing miR-200 [8]. An additional role of EMT in tumorigenesis might be the 38 development of apoptotic tolerance and increased resistance to chemotherapy as has been found in 39animal models and patients [8,9]. Recently, a hybrid stage between epithelial and mesenchymal 40 2 of 19 phenotypes (hybE/M) has been recognized, and such hybE/M cells migrate outside the primary 41 tumors displaying some mesenchymal features such as spindle-like morphology, increased nuclear 42 levels of ZEB1 transcription factor, and epithelial ones such as cell-cell adhesion potential [10,11]. 43In order to study the transitory stages of EMT, MET and hybE/M, in particular at in vivo settings, 44 there is need to generate reporter cells to visualize phenotypical changes. There have been different 45 approaches to this, for example the use of heterologous fluorescent proteins driven under stage-46 specific promoters such as mesenchymal (ZEB1) and epithelial (CDH1) [12], mesenchymal snai1 and 47 epithelial sox10 in zebrafish [13], or mesenchymal Vimentin (Vim) in mice [14]. Nevertheless, 48 hete...

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Section: Discussionsupporting

confidence: 92%

Genetical engineered lung cancer cell for analyzing Epithelial-Mesenchymal transition

Kiełbus

Czapiński

Kałafut

et al. 2019

Preprint

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“…It was demonstrated that miR-200c is down-regulated in TGF-β-treated or trastuzumab-resistant gastric cancer cells and targets ZEB1 and ZEB2. Therefore, over-expression of miR-200c can reverse trastuzumab resistance in gastric cancer cells [164]. Moreover, the over-expression of miR-200 family (miR-200a, miR-200b, and miR-429) was found to block the EMT process, thereby reversing therapeutic resistance, rather than impacting lung metastasis in an orthotopic breast tumor model [163] (Table 5).…”

Section: Mirnas Directly Regulating Emt-related Transcription Factorsmentioning

confidence: 99%

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

Seo

Moeng

Sim³

et al. 2019

Cells

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The susceptibility of cancer cells to different types of treatments can be restricted by intrinsic and acquired therapeutic resistance, leading to the failure of cancer regression and remission. To overcome this problem, a combination therapy has been proposed as a fundamental strategy to improve therapeutic responses; however, resistance is still unavoidable. MicroRNA (miRNAs) are associated with cancer therapeutic resistance. The modulation of dysregulated miRNA levels through miRNA-based therapy comprising a replacement or inhibition approach has been proposed to sensitize cancer cells to other anti-cancer therapies. The combination of miRNA-based therapy with other anti-cancer therapies (miRNA-based combinatorial cancer therapy) is attractive, due to the ability of miRNAs to target multiple genes associated with the signaling pathways controlling therapeutic resistance. In this article, we present an overview of recent findings on the role of therapeutic resistance-related miRNAs in different types of cancer. We review the feasibility of utilizing dysregulated miRNAs in cancer cells and extracellular vesicles as potential candidates for miRNA-based combinatorial cancer therapy. We also discuss innate properties of miRNAs that need to be considered for more effective combinatorial cancer therapy.Cells 2020, 9, 29 2 of 32 to confer the ability to acquire CSC properties onto cancer cells, thereby contributing to therapeutic resistance [7]. Moreover, cell-to-cell communication via extracellular vesicles among different types of cells within the cancer microenvironment could affect the efficacy of cancer therapies by delivering miRNAs that regulate various signaling pathways connected to therapeutic resistance [8,9].Combination therapies have been proposed to overcome therapeutic resistance via the combined inhibition of different mechanisms. For example, the combination of cobimetinib and pictilisib was reported to be beneficial for the treatment of colorectal cancer cells. However, resistance is unavoidable even after the combination treatment [10]. Similarly, the simultaneous inhibition of phosphoinositide 3-kinase (PI3K) and a mechanistic target of rapamycin kinase (mTOR) was reported to activate extracellular signal-regulated kinase (ERK), a pro-survival factor, in acute myeloid leukemia [11]. Therefore, it is still necessary to explore new combination strategies to defeat therapeutic resistance. An improved understanding of the cellular basis of cancer therapeutic resistance can further provide promising opportunities to design and develop novel cancer treatment strategies to manage cancers.MicroRNAs (miRNAs) are widely recognized, small, regulatory RNAs modulating numerous intracellular signaling pathways in several diseases, including cancers. Based on the expression levels and intracellular functions of miRNAs, they could act as tumor-suppressive or oncogenic factors in cancer cells [12][13][14]. The abnormal expression of miRNAs is associated with therapeutic resistance in cancer, and the modulation of m...

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“…Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer-associated mortality worldwide (1). The incidence and mortality rates of GC are the highest in East Asia, primarily in China (1)(2)(3). Gastric carcinogenesis is a complex process, which involves crosstalk among host, environmental and bacterial factors, leading to different molecular alterations at the genetic and epigenetic level; Helicobacter pylori is a well-recognized high-risk factor (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…Chemotherapy resistance frequently emerges as a cause of treatment failure (6). At present, the outcome for patients with advanced GC remains poor, with 5-20% 5-year survival and a median overall survival of 10 months (3). Therefore, examining novel biomarkers for early diagnosis and other feasible treatments based on a better understanding of mechanisms underlying GC pathogenesis, in addition to chemoresistance, is urgently required.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer (Review)

Zhu

Xiong

et al. 2019

Oncol Rep

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Gastric carcinogenesis arises from complicated interactions among host, environmental and bacterial factors, which cause genetic and epigenetic dysregulation of oncogenic and tumor-suppressive genes. MicroRNAs (miRNAs), a class of small non-coding RNAs that post-transcriptionally regulate ~30% human genes, may serve as oncogenes or tumor-suppressors in malignancies, including gastric cancer (GC). Although miRNA dysregulation commonly exists in GC, exact roles miRNAs serve in the pathogenesis and promotion of this tumor remain undetermined. Recently, results of previous studies regarding mechanisms underlying miRNAs generally converged on pathways critical in cellular processes, including cell proliferation, apoptosis and invasion, among which phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling is a fundamental one, with frequent oncogenic alterations in GC. Therefore, in the present review, the disorder and function of miRNAs and PTEN/PI3K/Akt signaling in GC are discussed. Additionally, how miRNAs transduce their effects by regulating this pathway, particularly in GC stem cells and the tumor microenvironment, and two novel hypotheses significant in carcinogenesis, tumor progression and recurrence, are discussed. Furthermore, the roles of miRNAs and the PTEN/PI3K/Akt pathway in target therapies against this lethal disease are outlined.

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miR-200c inhibits TGF-β-induced-EMT to restore trastuzumab sensitivity by targeting ZEB1 and ZEB2 in gastric cancer

Cited by 70 publications

References 31 publications

Genetical engineered lung cancer cell for analyzing Epithelial-Mesenchymal transition

Genetical engineered lung cancer cell for analyzing Epithelial-Mesenchymal transition

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer (Review)

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