Publications by authors named "Shubin Hong"

15 Publications

  • Page 1 of 1

The ETS Inhibitor YK-4-279 Suppresses Thyroid Cancer Progression Independent of Promoter Mutations.

Front Oncol 2021 16;11:649323. Epub 2021 Jun 16.

Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Hotspot mutations in the core promoter region of the () gene have been well established to associate with aggressive clinical characteristics, radioiodine refractory, tumor recurrence, and mortality in thyroid cancer. Several E-twenty-six (ETS) transcription factors were reported to selectively bound to the mutant promoter and activated TERT expression. In this study we aimed to investigate whether promoter mutations confer sensitivity to ETS inhibitor YK-4-279 in thyroid cancer cells and whether this inhibitor could be served as a potential therapeutic agent for thyroid cancer. assays showed that YK-4-279 treatment sharply suppressed cell viability, colony formation, migration, and invasion, as well as induced cell cycle arrest and apoptosis in a panel of thyroid cancer cells. The cell viability after YK-4-279 treatment was similar between cell lines harboring mutant and wild-type promoters. Furthermore, YK-4-279 treatment reduced both luciferase activity and mRNA expression of TERT independent of promoter mutation status. Data from RNA-seq further revealed that YK-4-279 significantly affected biological processes including DNA replication and cell cycle. Reduced DNA helicase activity and decreased expression of several helicase genes were observed after YK-4-279 treatment. Moreover, YK-4-279 significantly inhibited tumor growth and induced apoptosis in a xenograft mice model. Thus, ETS inhibitor YK-4-279 suppressed TERT expression and conferred anti-tumor activity in a promoter mutation-independent manner, and it could be a potential agent for the treatment of advanced thyroid cancers.
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http://dx.doi.org/10.3389/fonc.2021.649323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242932PMC
June 2021

Genome-Wide Histone H3K27 Acetylation Profiling Identified Genes Correlated With Prognosis in Papillary Thyroid Carcinoma.

Front Cell Dev Biol 2021 11;9:682561. Epub 2021 Jun 11.

Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Thyroid carcinoma (TC) is the most common endocrine malignancy, and papillary TC (PTC) is the most frequent subtype of TC, accounting for 85-90% of all the cases. Aberrant histone acetylation contributes to carcinogenesis by inducing the dysregulation of certain cancer-related genes. However, the histone acetylation landscape in PTC remains elusive. Here, we interrogated the epigenomes of PTC and benign thyroid nodule (BTN) tissues by applying H3K27ac chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) along with RNA-sequencing. By comparing the epigenomic features between PTC and BTN, we detected changes in H3K27ac levels at active regulatory regions, identified PTC-specific super-enhancer-associated genes involving immune-response and cancer-related pathways, and uncovered several genes that associated with disease-free survival of PTC. In summary, our data provided a genome-wide landscape of histone modification in PTC and demonstrated the role of enhancers in transcriptional regulations associated with prognosis of PTC.
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http://dx.doi.org/10.3389/fcell.2021.682561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226268PMC
June 2021

Utility of multi-parametric quantitative magnetic resonance imaging of the lacrimal gland for diagnosing and staging Graves' ophthalmopathy.

Eur J Radiol 2021 Aug 8;141:109815. Epub 2021 Jun 8.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong Province, China. Electronic address:

Purpose: To explore radiological changes of the lacrimal gland (LG) in Graves' ophthalmopathy (GO) based on multi-parametric quantitative MRI and its clinical utility in LG diagnosis and activity in GO.

Methods: We enrolled 99 consecutive patients with GO (198 eyes) and 12 Graves' Disease (GD) patients (24 eyes) from July 2018 to June 2020. Clinical, laboratory, and MRI data were collected at the first visit. Based on clinical activity scores, eyes with GO were subdivided into active and inactive groups. T2-relaxation time (T2) and the absolute reduction in T1-relaxation time (ΔT1) were determined. After MRI and processing, we performed descriptive data analysis and group comparisons. Novel logistic regression predictive models were developed for diagnosing and staging GO. Diagnostic performance of MRI parameters and models was assessed by receiver operating characteristic curve analysis.

Results: LG in GO group had significantly higher T2 and ΔT1 values than the GD group [106.25(95.30,120.21) vs. 83.35(78.15,91.45), P<0.001, and 662.62(539.33,810.95) vs. 547.35(458.62,585.57), P = 0.002, respectively]. The GO group had higher T2 of LG indicating higher disease activity [110.93(102.54,127.67) vs. 93.29(87.06,101.96), P < 0.001]. Combining T2 and ΔT1 values of LG, Model I had higher diagnostic value for distinguishing GO from GD (AUC=0.94, 95 %CI: 0.89,0.99, P<0.001). Meanwhile, T2 of LG had higher diagnostic value for grading GO activity (AUC = 0.84, 95 %CI: 0.76,0.92, P<0.001).

Conclusions: Multi-parametric quantitative MRI parameters of the LG in GO were significantly altered. Novel models combining LG T2 and ΔT1 values showed excellent predictive performances in diagnosing GO. Furthermore, T2 of LG showed practical utility for staging GO.
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http://dx.doi.org/10.1016/j.ejrad.2021.109815DOI Listing
August 2021

Corneal Endothelium: A Promising Quantitative Index for Graves Ophthalmopathy Activity Evaluation.

Am J Ophthalmol 2021 Jun 6;230:216-223. Epub 2021 Jun 6.

Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China. Electronic address:

Purpose: To investigate the corneal endothelium damage in Graves ophthalmopathy (GO) and its role as a promising quantitative index to evaluate GO activity.

Design: Cross-sectional study.

Methods: This study included 128 eyes of 64 patients with GO. All subjects underwent ophthalmologic examinations, including proptosis, tear break-up time (BUT), corneal fluorescein staining, and Schirmer test. Corneal endothelium was measured by noncontact specular microscope and ocular biometric parameters were measured by IOLMaster 700. Each eye was assigned a specific clinical activity score (CAS), then grouped as active (CAS ≥3 points) or inactive (CAS <3 points). Ocular parameters between the 2 groups were compared using generalized estimating equations accounting for inter-eye correlation, and receiver operating characteristic (ROC) curves were also obtained. Main outcome measures were parameters of corneal endothelium.

Results: Among the included eyes, 81 eyes had inactive GO and 47 eyes had active GO. Corneal endothelial cell morphology was altered in active GO compared with inactive GO. The coefficient variation of cell area (CV) was significantly higher in active GO compared with inactive GO (37.0 [34.4-41.2]% vs 33.9 [30.9-36.8]%, P = .001), and positively correlated with CAS (r = 0.322, P < .001). Moreover, CV showed a diagnostic capacity to differentiate the active eyes from inactive eyes. The area under the ROC curve was 0.705.

Conclusions: Active GO had morphologic changes in corneal endothelium compared with inactive GO. CV is a sensitive indicator to reflect corneal endothelial function, and has the potential to be adopted as a noninvasive, objective, and quantitative index for evaluating the activity status of GO patients.
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http://dx.doi.org/10.1016/j.ajo.2021.05.020DOI Listing
June 2021

Selenite Induces Cell Cycle Arrest and Apoptosis Reactive Oxygen Species-Dependent Inhibition of the AKT/mTOR Pathway in Thyroid Cancer.

Front Oncol 2021 21;11:668424. Epub 2021 May 21.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Thyroid cancer is the most common endocrine malignancy, and its incidence has increased in the past decades. Selenium has been shown to have therapeutic effects against several tumors. However, its role in thyroid cancer and its underlying molecular mechanism remains to be explored. In the present study, we demonstrated that sodium selenite significantly decreased cell viability and induced G0/G1 cell cycle arrest and apoptosis in thyroid cancer cells in a dose-dependent manner. Transcriptomics revealed that sodium selenite induced intracellular reactive oxygen species (ROS) by promoting oxidative phosphorylation. Increased intracellular ROS levels inhibited the AKT/mTOR signaling pathway and upregulated EIF4EBP3. Intracellular ROS inhibition by N-acetylcysteine (NAC) ameliorated the cellular effects of sodium selenite. The findings were reproduced in xenograft thyroid tumor models. Our data demonstrated that sodium selenite exhibits strong anticancer effects against thyroid cancer cells, which involved ROS-mediated inhibition of the AKT/mTOR pathway. This suggests that sodium selenite may serve as a therapeutic option for advanced thyroid cancer.
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http://dx.doi.org/10.3389/fonc.2021.668424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176115PMC
May 2021

Genetic alterations in cfDNA of benign and malignant thyroid nodules based on amplicon-based next-generation sequencing.

Ann Transl Med 2020 Oct;8(19):1225

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Circulating cell-free DNA (cfDNA) serves as a biomarker in multiple malignant diseases. However, controversy still surrounds the role of cfDNA detection in the diagnosis and monitoring of papillary thyroid carcinoma (PTC). This study set out to identify the role of cfDNA detection in distinguishing between benign and malignant thyroid nodules.

Methods: Tissue, blood cell, and plasma samples were collected from 10 patients with benign nodules and 10 patients with malignant nodules. The DNA isolated from these samples was subject to PCR-based amplification using primers designed for 50 proto-oncogenes and tumor suppressor genes. PCR products were sequenced using Illumina technology, and the mutations were detected with varScan among sequencing data for each sample and comparative analysis was carried out.

Results: Through amplicon sequencing, we found one non-synonymous somatic mutation in the benign nodules and three in the malignant nodules. Among these four mutations, BRAF mutation was detected in the tissue samples of 8 out of the 10 PTC patients, but it was not detected in the benign nodules. However, no BRAF mutation was detected in cfDNA. Further differential analysis of cfDNA indicated that some genes had more mutations in benign patients than in malignant patients, such as MET and IDH, and some genes had more mutations in malignant patients, such as PIK3CA and EZH2.

Conclusions: We found that BRAF mutation was a credible disease-related mutation in PTC; however, it could not be detected in cfDNA. Moreover, there was a large difference in mutation gene distribution between benign and malignant thyroid nodules.
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http://dx.doi.org/10.21037/atm-20-4544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607131PMC
October 2020

TET1 is a Tumor Suppressor That Inhibits Papillary Thyroid Carcinoma Cell Migration and Invasion.

Int J Endocrinol 2020 8;2020:3909610. Epub 2020 Feb 8.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.

Background: Ten-eleven translocation (TET) enzymes catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) promoting demethylation in cells. However, the expression pattern and biologic significance of TET in papillary thyroid carcinoma (PTC) remain unclear. This study aimed to elucidate the biological functions of TET1 and the miRNA and mRNA expression levels in PTC cells with downregulated TET1.

Methods: The expression of the TET family in 49 PTC tissues and corresponding tumor-adjacent tissues, as well as PTC cell lines (BCPAP, K1, and TPC-1) and the normal thyroid epithelial cell line (Nthy-ori 3-1), were detected using quantitative real-time polymerase chain reaction. The 5hmC level was detected in PTC tissues and cell lines using immunohistochemistry and dot blot assay, respectively. After silencing the gene with siRNAs in BCPAP and TPC-1 cells, cell proliferation was detected using EdU assay. Transwell assay was used to investigate cell migration and invasion. miRNA and mRNA expression arrays were conducted in TET1-depleted BCPAP cells.

Results: The expression level of TET1 decreased in PTC tissues and cell lines and was consistent with the reduction in the 5hmC level. The knockdown of the gene with siRNAs in BCPAP and TPC-1 cells, cell proliferation was detected using EdU assay. Transwell assay was used to investigate cell migration and invasion. miRNA and mRNA expression arrays were conducted in TET1-depleted BCPAP cells. , , , , and was upregulated as potential target genes of dysregulated miRNAs.

Conclusion: The study showed that TET1 dysfunction inhibited the migration and invasion of BCPAP cells and might have a potential role in the pathogenesis of PTC.
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http://dx.doi.org/10.1155/2020/3909610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031722PMC
February 2020

miR-3619-3p promotes papillary thyroid carcinoma progression via Wnt/β-catenin pathway.

Ann Transl Med 2019 Nov;7(22):643

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.

Background: It is well known that the dysregulation of microRNAs (miRNAs) has been identified in papillary thyroid carcinoma (PTC), but their roles in the progression and metastasis of PTC remain unclear. MicroRNA-3619-3p (miR-3619-3p) is associated with cancer progression as an oncogene which is predicted to target at the Wnt/β-catenin signaling pathway. Our study aimed to investigate the role of miR-3619-3p on PTC cell migration and invasion, as well as the underlying mechanisms.

Methods: The expression of miR-3619-3p in 36 PTC tissues and corresponding tumor-adjacent tissues, as well as 3 PTC cell lines (BCPAP, K1, TPC-1) and the normal thyroid epithelial cell line (N-thy-ori 3-1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between miR-3619-3p expression and clinicopathologic status of PTC patients was analyzed. Migration, invasion, and wound healing, were used to evaluate the role of miR-3619-3p in PTC. The activation of β-catenin and the possible molecular pathway were detected by western blotting.

Results: The expression of miR-3619-3p in PTC tissues was significantly higher than the corresponding tumor-adjacent tissues (P<0.01), and its high expression positively correlated with extrathyroidal invasion, multicentricity, and cervical lymph node metastasis. Moreover, the miR-3619-3p was also up-regulated in PTC cell lines when compared to N-thy-ori 3-1. MiR-3619-3p enhanced the capabilities of migration and invasion in PTC cell lines. Furthermore, miR-3619-3p activated Wnt/β-catenin pathway via maintaining the mRNA stability of β-catenin.

Conclusions: miR-3619-3p promoted PTC cell migration and invasion as an oncogene via activating the Wnt/β-catenin pathway through increasing the stability of β-catenin.
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http://dx.doi.org/10.21037/atm.2019.10.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944574PMC
November 2019

The potential targets for metastases: a study on altered circular RNA profile in breast cancer liver metastases.

Epigenomics 2019 08 11;11(11):1237-1250. Epub 2019 Jul 11.

Diagnosis & Treatment Center of Breast Diseases, Shantou Affiliated Hospital, Sun Yat-sen University, Shantou 515000, Guangdong, PR China.

To export the expression profile of circRNAs in breast cancer liver metastases (BCLM). RNA sequences were used to identify the altered expression profile of circRNAs in BCLM tissues and 231 liver metastasis cells. Quantitative PCR verified the expression of circRNAs in both BCLM tissues and 231 liver metastasis cells. The altered expressed circRNAs were found in BCLM tissues, compared with primary tumor tissues. These circRNAs involved in metastatic related signaling pathways. Hsa_circ_21439 and hsa_circ_11783 were verified to be the most significantly up- and downregulated circRNAs in both BCLM tissues and cells. circRNA/miRNA analysis revealed that has_circ_21439 and has_circ_11783 could act as 'miRNA sponge'. This study provides a potential diagnosis and therapy targets for BCLM.
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http://dx.doi.org/10.2217/epi-2019-0099DOI Listing
August 2019

MicroRNA-222 Promotes Invasion and Metastasis of Papillary Thyroid Cancer Through Targeting Protein Phosphatase 2 Regulatory Subunit B Alpha Expression.

Thyroid 2018 09 21;28(9):1162-1173. Epub 2018 Aug 21.

1 Department of Endocrinology, The First Affiliated Hospital of Sun Yat-Sen University , Guangzhou, China .

Background: Increasing evidence indicates that microRNA dysfunction is involved in the pathogenesis and progression of cancer. MicroRNA-222 (miR-222) is upregulated in papillary thyroid carcinoma (PTC). However, the role of miR-222 in invasion and metastasis of PTC remains unknown. This study investigated the function of miR-222 and its underlying mechanism in the progression of PTC.

Methods: The expression of miR-222 was detected by quantitative reverse transcription polymerase chain reaction, and its correlation with various clinical characteristics was analyzed. The role of miR-222 in PTC cell migration ability was assessed with Transwell assays and wound-healing assays in both TPC-1 and K1 cells. By using bioinformatics analyses and dual-luciferase 3'-UTR reporter assays, the study identified the direct target of miR-222 and the downstream pathways of PTC. Further, the study confirmed the role of miR-222 in promoting PTC distant metastasis in vivo by injecting TPC-1 cells into nude mice.

Results: This study confirmed that miR-222 was upregulated in PTC tissues compared to adjacent thyroid tissues and that it correlated with aggressive cancer phenotypes. The results indicate that ectopic miR-222 enhanced cell migration and invasion of thyroid cancer cells in vitro and distant pulmonary metastases in vivo. Protein phosphatase 2 regulatory subunit B alpha (PPP2R2A), a tumor suppressor, was identified as a direct target of miR-222 through the 3'-UTR of PPP2R2A. Restoring PPP2R2A expression led to the attenuation of migration and invasion in miR-222-overexpressing thyroid cancer cells. Moreover, we found that miR-222 promoted invasion and metastasis partly through the AKT signaling pathway.

Conclusions: Taken together, the results suggest that miR-222 promotes tumor invasion and metastasis in thyroid cancer by targeting PPP2R2A. Thus, miR-222 could serve as a potential diagnostic biomarker, as well as an attractive therapeutic tool for thyroid cancer.
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http://dx.doi.org/10.1089/thy.2017.0665DOI Listing
September 2018

Inhibits Tumor Growth and Metastasis in Papillary Thyroid Carcinoma Cell Lines by Targeting and .

Int J Endocrinol 2017 27;2017:6180425. Epub 2017 Jun 27.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.

Background: MicroRNA (miRNA) dysregulation was commonly seen in papillary thyroid carcinoma (PTC), and was verified to be downregulated in PTC by the large data set analysis from The Cancer Genome Atlas (TCGA). Our study aimed to explore the biological functions and the underlying molecular mechanisms of in PTC.

Methods: The relative expression of and its target genes were assessed by quantitative RT-PCR assay in 38 pairs of PTC and the adjacent thyroid tissues. Assays were performed to evaluate the effect of on the proliferation, migration, and invasion in PTC cell lines. Moreover, we searched for targets of and explored the possible molecular pathway of in PTC.

Results: We found that was downregulated in PTC cell lines and tissues. Overexpression of significantly inhibited cell proliferation, migration, and invasion in K1 and BCPAP cell lines. and , which had inverse correlations with in clinical specimens, were found to be the direct targets of . Furthermore, might be involved in PTC tumorigenesis by suppressing the Wnt/-catenin signaling pathway.

Conclusions: These results highlight an important role of in the initiation and progression of PTC and implicate the potential application of in PTC target therapy.
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http://dx.doi.org/10.1155/2017/6180425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504932PMC
June 2017

Plasma apolipoprotein A1 levels at diagnosis are independent prognostic factors in invasive ductal breast cancer.

Discov Med 2017 04;23(127):247-258

Diagnosis and Treatment Center of Breast Diseases, Shantou Affiliated Hospital of Sun Yat-Sen University, Shantou, Guangdong, China.

Strong evidence exists indicating that the risk of breast cancer (BC) occurrence is influenced by complex internal environmental factors, including blood lipid and lipoprotein components. However, the roles of these components in BC development and progression remain controversial. This study examined whether serial serum lipid and lipoprotein measurements were associated with breast cancer risk and whether lipoproteins had BC prognostic properties. We compared the plasma-related parameter levels, including lipid and lipoprotein levels between 299 patients with invasive ductal breast cancer, also known as invasive ductal carcinoma (IDC), and 200 healthy donors. We performed univariate and multivariate logistic regression analyses to assess overall survival (OS) and disease-free survival (DFS). We found that the serum glucose, triacylglycerol, and low-density lipoprotein levels were significantly higher in patients with IDC than in healthy donors. However, high-density lipoprotein and apolipoprotein A1 (apoA1) levels were lower in patients with IDC than in healthy donors. Multivariate regression analysis demonstrated that elevated apoA1 levels were associated with a reduced risk of IDC, and univariate analysis showed that patients with IDC with lower apoA1 levels at diagnosis had larger tumors than patients with high apoA1 levels. Moreover, patients with IDC with lower apoA1 levels were more likely to have positive axillary lymph nodes, and were diagnosed at more advanced disease stages than patients with high apoA1 levels. We used a Cox regression model to assess the relationships between the above parameters and DFS and OS, after adjusting for tumor T and N stages, which were determined using the TNM classification system, and immunohistochemical subtypes. We found that lower apoA1 levels at diagnosis were associated with poor DFS and OS. At 60 months of follow-up, the DFS rate is 74.5% in the apoA1 L1 group, 89.9% in apoA1 L2 group, and 93.1% in apoA1 L3 group (p=0.0002). Similarly, the OS rate is 78.2% in apoA1 L1 group, 91.3% in apoA1 L2 group, and 93.7% in apoA1 L3 group (p=0.0012). In conclusion, our data indicate that low apoA1 levels are an independent predictor of the poor clinical outcomes in IDC patients.
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April 2017

MiR-20b Displays Tumor-Suppressor Functions in Papillary Thyroid Carcinoma by Regulating the MAPK/ERK Signaling Pathway.

Thyroid 2016 12 2;26(12):1733-1743. Epub 2016 Nov 2.

1 Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University , Guangzhou, China .

Background: MicroRNAs (miRNAs) are endogenous, small, non-coding RNAs that play important roles in multiple biological processes. MiR-20b has been reported to be dysregulated in papillary thyroid carcinoma (PTC). However, the functional roles are still largely unknown. This study aimed to investigate the biological functions and the underlying molecular mechanisms of miR-20b in PTC.

Method: The expression of miR-20b was assessed by quantitative reverse transcription polymerase chain reaction in 47 pairs of PTC and adjacent normal thyroid tissues. The association between miR-20b expression and clinicopathologic status of PTC patients was analyzed. MiR-20b was overexpressed in the PTC cell lines K1 and TPC-1, and the effects on cell viability, migration, and invasion were evaluated. The study further searched for targets of miR-20b, and identified the possible molecular mechanisms of miR-20b in PTC cells. Additionally, the effect of miR-20b on tumor growth in nude mice was assessed.

Results: It was found that miR-20b was markedly downregulated in PTC tissues compared with their adjacent normal thyroid tissues. The low-level expression of miR-20b was correlated with cervical lymph node metastasis and TNM staging. Upregulation of miR-20b inhibited cell viability, migration, and invasion in K1 and TPC-1 cells. Ectopic overexpression of miR-20b could suppress the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway through directly targeting son of sevenless homolog 1 (SOS1) and extracellular signal-regulated kinase 2 (ERK2). Furthermore, depletion of SOS1 or ERK2 by siRNAs has similar effects as miR-20b overexpression on cell viability and invasion, whereas rescued SOS1 or ERK2 expression partially reversed the inhibitory effects of miR-20b in TPC cell lines. In xenograft animal experiments, it was found that overexpressed miR-20b could suppress tumor growth of PTC cells.

Conclusion: These results indicate for the first time that miR-20b displays tumor-suppressor functions in PTC. By targeting SOS1 and ERK2, miR-20b inhibits the activity of the MAPK/ERK signaling pathway. The findings suggest that miR-20b may play an important role in PTC initiation, progression, and metastasis, and may provide a potential therapeutic target for PTC.
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http://dx.doi.org/10.1089/thy.2015.0578DOI Listing
December 2016

A systematic review and meta-analysis of the risk of diarrhea associated with vandetanib treatment in carcinoma patients.

Onco Targets Ther 2016 20;9:3621-31. Epub 2016 Jun 20.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.

Background And Purpose: Vandetanib is a promising anticancer targeted agent for treating advanced carcinomas, such as non-small-cell lung cancer, small-cell lung cancer, breast cancer, malignant glioma, hepatocellular cancer, and unresectable, locally advanced, or metastatic medullary thyroid cancer. However, diarrhea is a frequently reported adverse event. The incidence of vandetanib-associated diarrhea varies extensively in different study populations and has not been carefully estimated. This systematic review and meta-analysis of clinical trials aims to figure out the overall risks of all-grade and high-grade diarrhea during vandetanib treatment and get a better understanding of its prediction and management.

Materials And Methods: A comprehensive search was performed in EMBASE, PubMed, and Cochrane Library for clinical trials studying vandetanib and diarrhea prior to April 2015. Eligible articles were selected according to the inclusion criteria. Data were extracted to calculate the summary incidence of all-grade and high-grade diarrhea caused by vandetanib treatment.

Results: Thirteen clinical trials that involved 3,264 patients were included in this meta-analysis. The overall incidences of all-grade and high-grade diarrhea caused by vandetanib treatment were 52.1% (95% confidence interval [CI], 48.3%-55.8%) and 5.6% (95% CI, 4.4%-76.7%), respectively. The risk ratios of the all-grade and high-grade diarrhea for vandetanib arm versus control arm were 1.932 (95% CI, 1.746-2.138; P<0.001) and 3.190 (95% CI, 2.061-4.938; P<0.001), respectively. Studies with small-cell lung cancer demonstrated the highest incidence of all-grade diarrhea (78.85%) and high-grade diarrhea (17.31%), whereas the lowest incidences of all-grade (42.11%) and high-grade (2.67%) diarrhea are seen in patients with hepatocellular carcinoma and non-small-cell lung cancer, respectively.

Conclusion: Our findings demonstrate that the administration of vandetanib leads to a significantly increased risk of diarrhea, which varies in different carcinoma patients. Early recognition and timely management may be key factors to avoid dose reduction, drug interruption, and drug discontinuation, which is significant to maximize the treatment benefits.
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http://dx.doi.org/10.2147/OTT.S96830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920236PMC
July 2016

17β-Estradiol inhibits vascular smooth muscle cell migration via up-regulation of striatin protein.

Gynecol Endocrinol 2015 29;31(8):618-24. Epub 2015 Jul 29.

e School of Basic Sciences, Guangzhou Medical University , Guangzhou , Guangdong Province , China.

Striatin, an estrogen receptor (ER)-interacting protein, plays an important role in estrogen's nongenomic actions in vascular endothelial cells. However, the role of striatin in VSMCs is unknown. Here, we investigated the role of striatin in estrogen-regulated VSMCs migration. 17β-Estradiol (E2) at 10 nM largely inhibited VSMCs migration, which was reversed by the silencing of striatin expression. E2 increased striatin protein expression in a dose- and time-dependent manner. ERα agonist PPT, but not ERβ agonist DPN, mimicked the regulatory effect of E2. The regulatory effect of E2 on striatin protein expression was blocked by the pure ER antagonist ICI 182,780 or the mitogen-activated protein kinase inhibitor PD98059, but not by the phosphatidylinositol-3 kinase inhibitor wortmannin or Src inhibitor PP2, suggesting that E2 increased striatin protein expression via extracellular-signal regulated kinase 1/2 (ERK1/2). E2 resulted in phosphorylation of ERK1/2 in a time-dependent manner. The silencing of ERK1/2 largely abolished E2-enhanced striatin expression. Finally, the inhibitory effect of E2 on VSMC migration was reversed by ICI 182,780 or PD98059. Taken together, our results indicate that E2 inhibits VSMC migration by increasing striatin expression via ERα to ERK1/2 pathway, which maybe helpful to understand estrogen's anti-atherogenic effect in VSMCs.
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http://dx.doi.org/10.3109/09513590.2015.1021325DOI Listing
July 2016
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