MiR-146b-5p Promotes Metastasis and Induces Epithelial-Mesenchymal Transition in Thyroid Cancer by Targeting ZNRF3

Deng, Xianzhao; Wu, Bo; Ke, Xiaoyan; Kang, Jie; Xie, Jing; Zhang, Xiaoping; Fan, Youben

doi:10.1159/000369676

Cited by 134 publications

(120 citation statements)

References 25 publications

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“…However, it is not clear how TSHR suppresses EMT. Previous studies have demonstrated that microRNA (miRNA/miR) serves an important role in EMT; for example, miR-146b-5p induces EMT through the regulation of Wnt/β-catenin signaling (19,20) and the miR-200 family inhibits polycomb complex protein BMI1, and zinc finger E-box-binding homeobox 1 and 2, to suppress EMT (21)(22)(23). Further studies are required to demonstrate whether TSHR regulates EMT through miRNAs.…”

Section: Discussionmentioning

confidence: 99%

Downregulated expression of TSHR is associated with distant metastasis in thyroid cancer

Liu

Men

et al. 2017

Oncol Lett

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Abstract. In differentiated thyroid cancer (DTC), the association between thyroid-stimulating hormone receptor (TSHR) and metastasis, and the underlying molecular mechanisms remain unclear. The role of TSHR in the epithelial-mesenchymal transition (EMT) has not yet been reported, to the best of our knowledge. In the present study, the role of TSHR in the distant metastasis of DTC was investigated. TSHR was significantly downregulated in well-differentiated thyroid cancer cells and tissues, and a lack of TSHR promoted thyroid cancer cell invasion and metastasis by inhibiting the EMT of thyroid cancer cells. In addition, the prognostic value of TSHR in thyroid cancer was analyzed. Immunohistochemical analysis of 172 DTC tissues revealed that a lack of expression of TSHR was associated with distant metastasis and a poor survival rate. Multivariate analyses demonstrated that TSHR expression was a significant prognostic factor for distant metastasis and survival time. The results from the present study demonstrated that TSHR inhibits metastasis through regulating EMT in vitro, and that a lack of expression of TSHR is a significant independent factor affecting distant metastasis and poor prognosis in DTC.

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Section: Discussionmentioning

confidence: 99%

Downregulated expression of TSHR is associated with distant metastasis in thyroid cancer

Liu

Men

et al. 2017

Oncol Lett

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“…64 MicroRNAs are increasingly recognized as important regulators of EMT and of CSCs. [65][66][67][68][69][70] Recent studies have shown that the miR-200 family has a major regulatory role in EMT. 65 The miR-200 family has been shown to regulate EMT induced by EGF/EGFR 66 and also by targeting TGFβR1.…”

Section: Non-coding Rnas and Emt Micrornas And Emtmentioning

confidence: 99%

“…MiRNAs also have regulatory roles in well-differentiated thyroid cancers during EMT. [68][69][70] MiR-146b-5p has been shown to regulate PTC cells during EMT. 69 Hardin et al 36 used a TGFβ-induced model of EMT to show that miR-146b-5p was initially upregulated during the first fourteen days of TGFβ treatment, which was followed by downregulation of this microRNA with subsequent treatment for two weeks.…”

Section: Non-coding Rnas and Emt Micrornas And Emtmentioning

confidence: 99%

“…[68][69][70] MiR-146b-5p has been shown to regulate PTC cells during EMT. 69 Hardin et al 36 used a TGFβ-induced model of EMT to show that miR-146b-5p was initially upregulated during the first fourteen days of TGFβ treatment, which was followed by downregulation of this microRNA with subsequent treatment for two weeks. Deng et al 69 later showed that miR-146b-5p targeted ZNRF3, increased the cell surface Wnt receptors Frizzled-6 and LRP6 and decreased Wnt/β-catenin signaling, as an inhibitor of Wnt/β-catenin suppressed the effect of miR-146b-5p on migration, invasiveness and EMT induction in PTC cell lines.…”

Section: Non-coding Rnas and Emt Micrornas And Emtmentioning

confidence: 99%

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The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

Hardin

Zhang

Helein

et al. 2017

Laboratory Investigation

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The cancer stem-like cell (CSC) hypothesis postulates that a small population of cells in a cancer has self-renewal and clonal tumor initiation properties. These cells are responsible for tumor initiation, growth, recurrence and for resistance to chemotherapy and radiation therapy. CSCs can be characterized using markers such as SSEA-1, SSEA-4, CD44, CD24, ALDEFLUOR and others. CSCs form spheres when they are cultured in serum-free condition in low attachment plates and can generate tumors when injected into immune-deficient mice. During epithelial to mesenchymal transition (EMT), cells lose cellular adhesion and polarity and acquire an invasive phenotype. Recent studies have established a relationship between EMT and increased numbers of CSCs in some solid malignancies. Non-coding RNAs such as microRNAs and long non-coding RNAs (lncRNAs) have been shown to have important roles during EMT and some of these molecules also have regulatory roles in the proliferation of CSCs. Specific lncRNAs enhanced cell migration and invasion in breast carcinomas, which was associated with the generation of stem cell properties. The tumor microenvironment of CSCs also has an important role in tumor progression. Recent studies have shown that the interaction between tumor cells and the local microenvironment at the metastatic site leads to the development of premetastatic niche(s) and allows for the proliferation of the metastatic cells during colonization. The role of exosomes in the microenvironment during the EMT program is currently a major area of research. This review examines CSCs and the relationship between EMT and CSCs in solid tumors with emphasis on thyroid CSCs. The role of non-coding RNAs and of the microenvironment in EMT and in tumor progression are also examined. This review also highlights the growing number of studies that show the close association of EMT and CSCs and the role of exosomes and other elements of the tissue microenvironment in CSC metastasis. A better understanding of these mechanisms will lead to more effective targeting of primary and metastatic malignancies.

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“…The prognosis of PTC patients is associated with their age, tumor size, lymph node invasion and distant metastasis (7). Currently, the standard therapeutic treatment for PTC is complete thyroidectomy followed by radioiodine and levothyroxine therapy (8).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑335 is downregulated in papillary thyroid cancer and suppresses cancer cell growth, migration and invasion by directly targeting ZEB2

Kan

Yang

2017

Oncol Lett

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Abstract. MicroRNAs (miRs) are a group of short, endogenous, non-protein-coding and single-stranded RNAs that regulate gene expression by binding to the 3'-untranslated region (3'UTR) of mRNAs, which results in their degradation or translational repression. The aim of the present study was to investigate the expression and function of miR-335 in human papillary thyroid cancer (PTC). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to quantify the relative miR-335 expression levels in PTC tissues and cell lines. The effect of miR-335 on the proliferation, migration and invasion of PTC cells was assessed by an MTT assay, and transwell migration and invasion assays, respectively. Dual-luciferase reporter assays were employed to explore whether miR-335 directly targeted the 3'UTR of the potential target gene zinc finger E-box binding homeobox 2 (ZEB2). RT-qPCR and western blotting were adopted to assess the effect of miR-335 on the mRNA and protein expression of ZEB2. RT-qPCR revealed that miR-335 was downregulated in PTC tissues and cell lines. The MTT assay and transwell migration and invasion assays demonstrated that the overexpression of miR-335 significantly inhibited the proliferation, migration and invasion of PTC cells. ZEB2 was identified as a direct target of miR-335 with computational analysis, which was confirmed with a dual-luciferase reporter assay, RT-qPCR and western blotting. The knockdown of ZEB2 significantly inhibited the proliferation, migration and invasion of PTC cells, indicating that ZEB2 may be a functional target of miR-335. Taken together, these findings suggested that miR-335 functioned as a tumor suppressor and suppressed the growth and metastatic behavior of PTC cells by targeting ZEB2. IntroductionThyroid cancer is the most common subtype of endocrine malignancy, with 300,000 new cases per year, and ~40,000 mortalities per year, worldwide (1). The incidence of thyroid cancer has increased in recent decades (2). It can be categorized into four major histologic groups, including papillary thyroid cancer (PTC), follicular thyroid cancer, poorly differentiated carcinoma and anaplastic thyroid cancer (3). PTC accounts for 80-90% of all thyroid cancer cases (4).A number of factors have been demonstrated to be associated with PTC progression, including genetic factors, environmental exposure, epigenetic alteration, nodular disease of the thyroid and radiation exposure (5,6). The prognosis of PTC patients is associated with their age, tumor size, lymph node invasion and distant metastasis (7). Currently, the standard therapeutic treatment for PTC is complete thyroidectomy followed by radioiodine and levothyroxine therapy (8). However, ~10% of patients with PTC develop recurrence and metastasis, which are associated with poor prognosis (9). Thus, it is necessary to characterize the molecular mechanisms of PTC initiation and development, and to develop novel, targeted therapies for PTC.The abnormal expression of microRNAs (miRNAs/miRs) has been implicated in ...

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MiR-146b-5p Promotes Metastasis and Induces Epithelial-Mesenchymal Transition in Thyroid Cancer by Targeting ZNRF3

Cited by 134 publications

References 25 publications

Downregulated expression of TSHR is associated with distant metastasis in thyroid cancer

Downregulated expression of TSHR is associated with distant metastasis in thyroid cancer

The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

MicroRNA‑335 is downregulated in papillary thyroid cancer and suppresses cancer cell growth, migration and invasion by directly targeting ZEB2

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