TAGLN2 promotes papillary thyroid carcinoma invasion via the Rap1/PI3K/AKT axis.

TAGLN2, an actin-binding protein, functions as a binding protein to actin to facilitate the formation of intracellular cytoskeleton structures. TAGLN2 overexpression in papillary thyroid carcinoma (PTC) is reported in our previous study. This study aimed to examine the functions and molecular mechanisms of TAGLN2 in PTC. The clinical data analysis showed that TAGLN2 expression was associated with cervical lymph node metastasis in PTC. Gain- and loss-of-function approaches, as well as various cellular function, gene expression profiles, quantitative proteomics, and molecular biology experiments, were further exploited to explore the roles of TAGLN2 in PTC. The results showed that TAGLN2 overexpression significantly promoted the invasion of PTC cell lines (K1, TPC-1, and BCPAP). Besides, the results also indicated that TAGLN2 was associated with regulating proliferation, migration, angiogenesis, and adhesion of PTC cells. Gene expression profile, quantitative proteomics, and Western blotting were performed to identify the relevant pathways and key downstream molecules, and Rap1/PI3K/AKT signalling pathway, ITGB5, LAMC2, CRKL, vimentin, N-cadherin, and E-cadherin were finally focused on. Moreover, rescue experiments validated the involvement of the Rap1/PI3K/AKT signalling pathway in the TAGLN2-mediated invasion of PTC cells. Therefore, TAGLN2 may promote the invasion of PTC cells via the Rap1/PI3K/AKT signalling pathway and may be served as a potential therapeutic target for PTC. Developing antagonists targeting TAGLN2 may be a potentially effective therapeutic strategy for PTC.

MiR-613 inhibits the proliferation, migration, and invasion of papillary thyroid carcinoma cells by directly targeting TAGLN2.

BACKGROUND: Papillary thyroid carcinoma (PTC), with a rapidly increasing incidence, is the most prevalent malignant cancer of the thyroid. However, its pathogenesis is unclear and its specific clinical indicators have not yet been identified. There is increasing evidence that microRNAs (miRNAs) play important roles in tumor occurrence and progression. Specifically, miR-613 participates in the regulation of tumor development in various cancers; however, its effects and mechanisms of action in PTC are still unclear. Therefore, in this study, we investigated the expression and function of miR-613 in PTC. METHODS: qRT-PCR was used to determine miR-613 expression in 107 pairs of PTC and adjacent-normal tissues as well as in PTC cell lines and to detect TAGLN2 mRNA expression in PTC tissues and adjacent normal tissues. Western blot analysis was performed to identify TAGLN2 and epithelial-mesenchymal transition (EMT) biomarkers. The effects of miR-613 on PTC progression were evaluated by performing MTS, wound-healing, and Transwell assays in vitro. Luciferase reporter assays were also performed to validate the target of miR-613. RESULTS: In PTC, miR-613 was significantly downregulated and its low expression level was associated with cervical lymph node metastasis. However, its overexpression significantly suppressed PTC cell proliferation, migration, and invasion and inhibited EMT. TAGLN2 was identified as a target of miR-613, which also significantly inhibited the expression of TAGLN2. Further, the restoration of TAGLN2 expression attenuated the inhibitory effects of miR-613 on PTC cell proliferation and metastasis. CONCLUSION: Our findings demonstrated that miR-613 can suppress the progression of PTC cells by targeting TAGLN2, indicating that miR-613 plays the role of a tumor suppressor in PTC. Overall, these results suggest that the upregulation of miR-613 is a promising therapeutic strategy for PTC.

MicroRNA-219a-2-3p modulates the proliferation of thyroid cancer cells via the HPSE/cyclin D1 pathway.

Heparanase (HPSE) is an endo-ß-D-glucuronidase overexpressed in different types of human cancer, and a predicted target of microRNA (miRNA/miR)-219a-2-3p in thyroid cancer. The present study aimed to investigate the potential role of HPSE and miR-219a-2-3p in thyroid cancer, and the molecular mechanism of miR-219a-2-3p regulating the proliferation of thyroid cancer cells via HPSE was confirmed. Immunohistochemistry analysis was performed to detect HPSE expression in thyroid cancer sections. In addition, reverse transcription-quantitative PCR analysis was performed to detect mRNA and miR-219a-2-3p expression levels in thyroid cancer samples and cell lines. miR-219-2-3p mimic or HPSE plasmid were transfected into B-CPAP and TPC-1 thyroid cancer cells. Furthermore, western blot analysis was performed to detect the protein expression levels of HPSE and cyclin D1. Cell cycle analysis was performed using propidium iodide staining and flow cytometry, and EdU incorporation was performed to detect cell proliferation. The results demonstrated that high HPSE expression was significantly associated with tumor size, extracapsular invasion and lymph node metastasis. Notably, a statistically negative correlation was observed between HPSE mRNA expression and miR-219a-2-3p expression in thyroid cancer tumors, as well as in thyroid cancer cell lines. When exogenously expressed in B-CPAP and TPC-1 cells, miR-219a-2-3p induced cell cycle arrest at the G0/G1 phase and decreased the percentage of proliferating cells. Furthermore, HPSE and cyclin D1 protein expression decreased following transfection with miR-219a-2-3p. Notably, when HPSE was ectopically expressed in miR-219a-2-3p transfected cells, cyclin D1 expression and the number of proliferative cells increased. Taken together, these results suggest that HPSE contributes to the proliferation of thyroid cancer cells. In addition, miR-219a-2-3p was confirmed to target HPSE and inhibit cell proliferation, which was associated with cyclin D1 suppression-mediated cell cycle arrest.

Deltex3 inhibits Epithelial Mesenchymal Transition in Papillary Thyroid Carcinoma via promoting ubiquitination of XRCC5 to regulate the AKT signal pathway.

Background: Papillary thyroid carcinoma (PTC) is one of the most common endocrine malignant tumors. Poor prognoses such as high recurrence rate always appear in PTC patients with cervical lymph node metastasis. The process of ubiquitination plays important roles in PTC. As ubiquitin E3 ligases, Deltex (DTX) family proteins were reported to associate with multiple cancers. However, functions and mechanisms of DTX3 in PTC are currently unknown. Methods: In this study, DTX3 expressions were examined in 114 PTC and paired paracancerous normal tissues through quantitative real-time polymerase chain reaction and western blot. The clinical significances of DTX3 expressions in PTC patients were also investigated. After stable transfection with either short hairpin RNA to knock down DTX3 expression or full-length complementary DNA to upregulate DTX3 expression, changes of malignant phenotypes in two PTC cell lines K1 and TPC-1 were observed using cell viability, flow cytometry, wound healing and transwell assays. Afterwards, altered expressions of epithelial-mesenchymal transition (EMT) and AKT signal pathway related proteins were measured by western blot. Immunoprecipitation and mass spectrometry (IP-MS), immunofluorescence and Co-IP were utilized to identify the possible DTX3 interacting proteins. Results: Both mRNA and protein expressions of DTX3 were lower in PTC tissues and correlated with the presence of cervical lymph node metastasis (P<0.05). DTX3 overexpression inhibited migration and invasion of PTC cells, decreased Vimentin and phosphorylated AKT expressions, but promoted E-cadherin expression (P<0.05). Moreover, knockdown of DTX3 led to opposite changes (P<0.05). Total 46 probable DTX3 interacting proteins were identified by IP-MS. Among them, X-ray repair cross-complementing protein 5 (XRCC5) and NADH: Ubiquinone Oxidoreductase Complex Assembly Factor 5 (NDUFAF5) were verified to be associated with DTX3. Moreover, DTX3 was proved to be co-localized with XRCC5 in nucleus and promote ubiquitination of XRCC5. Conclusions: DTX3 suppresses EMT by partially facilitating ubiquitination of XRCC5 to inhibit AKT signal pathway in PTC.

Effect of Banxia Baizhu Tianma Tang for H-type hypertension: A protocol for a systematic review.

BACKGROUND: H-type hypertension is a kind of cardiovascular disease that threatens human life and health seriously. Banxia Baizhu Tianma Tang (BBTT) has been used widely for H-type hypertension while its effective evidence is not clear. Hence, we provide a systematic review protocol to evaluate the efficacy and safety of BBTT in the treatment of H-type hypertension. METHODS: Nine databases including Cochrane Library, PubMed, EMBASE, WOS, Medline, CNKI, WangFang, CBM, and VIP will be searched from their inception to October 2019. All randomized controlled trials (RCTs) of BBTT for H-type hypertension will be included. The language is limited to Chinese and English. The primary outcome measure will be the major adverse cardiac and cerebral events (MACCE). The entire process will include study selection, data extraction, assessment of bias risk, data synthesis. Data analysis will be performed using RevMan V.5.3.5 (The Cochrane Collaboration, Oxford, UK). RESULTS: This study will evaluate the efficacy and safety of BBTT in the treatment of H-type hypertension from several aspects, including MACCE, blood pressure (BP), blood lipids, inflammation indicators and homocysteine (Hcy). CONCLUSION: This systematic review will provide evidence for determining whether or not BBTT is an effective and safe intervention for H-type hypertension. PROSPERO REGISTRATION NUMBER: PROSPERO CRD 42019131491.

Qinwen Baidu decoction for sepsis: A protocol for a systematic review and meta-analysis.

BACKGROUND: Sepsis is the most common critical illness in the clinic, with a high incidence and mortality. Qingwen Baidu decoction (QWBDD) has been widely applied in the treatment of sepsis, however, there is no systematic review or meta-analysis of QWBDD in the treatment of sepsis. Hence, we provide a protocol of systematic review and meta-analysis to evaluate the efficacy and safety of QWBDD in the treatment of sepsis. METHODS: The databases including Cochrane Library, PubMed, Embase, Web of Science, Cochrane Clinical Trial Database, World Health Organization International Clinical Trial Registration Platform, CNKI, CBM, VIP, and WanFang Database will be searched from the time when the respective databases were established to January 2019. All randomized controlled trials (RTCs) published in Chinese and English assessing QWBDD for sepsis will be included. Continuity data are expressed as mean difference (MD) or standard mean difference (SMD), and dichotomous data is expressed as relative risk. Analyses will be performed by using RevMan V.5.3.5 software. RESULTS: This study will provide high-quality synthesis of current evidence of QWBDD in the treatment of sepsis from the following aspects, including 28-day mortality, mean arterial pressure (MAP), blood lactate, procalcitonin (PCT), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), hypersensitive C-reactive protein (hs-CRP), acute physiology and chronic health score (APACHE-II), intensive care unit stay, mean hospital stay, mechanical ventilation time, etc. CONCLUSION:: Our systematic review will provide evidence for judging whether QWBDD is an effective intervention for sepsis. PROSPERO REGISTRATION NUMBER: PROSPERO CRD 42019123078.

Herbal medicine (Zhengan Xifeng Decoction) for essential hypertension protocol for a systematic review and meta-analysis.

BACKGROUND: Essential hypertension is one of the most common chronic diseases worldwide, as well as a leading risk factor for cardiocerebrovascular diseases. Zhengan Xifeng Decoction (ZGXFD) has been widely used to treat essential hypertension, but there is no systematic review by assessing efficacy and safety of ZGXFD on essential hypertension. Therefore, we aim to perform systematic review and meta-analysis to evaluate the efficacy and safety of ZGXFD in the treatment of essential hypertension. METHODS: This systematic review and meta-analysis will be performed by means of electronic databases, including EMBASE, Cochrane Center Registration Controlled trials (Cochrane Library), Web of Science (WOS), World Health Organization International Clinical Trials Registry Platform, PubMed, China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wan-fang database. The electronic databases will be searched from their inception to October 2018. This systemic review will include only published English and Chinese articles randomized controlled trials (RTCs) of ZGXFD on essential hypertension. The primary outcome is Efficacy and blood pressure (BP), blood lipid and adverse reactions will be accepted as secondary outcomes. All statistical analyses will be conducted using RevMan V.5.3.5 software. RESULTS: This systematic review and meta-analysis will provide high-quality evidence from several aspects, including for efficacy, blood pressure, blood lipid and adverse effects to evaluate the efficacy and safety of ZGXFD on EHTN. CONCLUSION: This systematic review will determine whether or not ZGXFD is an effective intervention for essential hypertension.

Expression of activator protein-1 in papillary thyroid carcinoma and its clinical significance.

BACKGROUND: The abnormal expression of activator protein-1(AP-1) has recently been investigated in a variety of tumors. While the relationship between AP-1 and thyroid cancer is poorly studied, our study was to evaluate the protein expression and clinical value of AP-1 in papillary thyroid carcinoma (PTC). METHODS: The expression of AP-1 was examined by immunohistochemistry on paraffin-embedded tissues obtained from PTC and correspondent paracancerous tissues of 82 patients. RESULTS: Compared with paracancerous tissues, AP-1 expression was significantly elevated in PTC tissues and the positive rate was 79.3% (65/82). Our study found a linear trend relationship between the expression of AP-1 and tumor size. However, the differences in AP-1 expression among gender, age, lymph node metastasis, number of lesions, location of the lesion, and extrathyroid invasion are not statistically significant. CONCLUSIONS: The expression of AP-1 plays an important role in the proliferation process of PTC.

Herbal medicine (zhishi xiebai guizhi decoction) for unstable angina: Protocol for a systematic review and meta-analysis.

BACKGROUND: Unstable angina (UA) is a clinically common coronary heart disease. Zhishi xiebai guizhi decoction (ZXGD) has been widely used in the management of UA, although its effective evidence is not clear and there is no systematic review regarding its efficacy and safety. Therefore, we conduct this systematic review protocol to evaluate the efficacy and safety of ZXGD in the treatment of UA. METHODS: We will search the following electronic databases: Cochrane Library, Web of Science, PubMed, EBASE, Springer, WHO International Clinical Trial Registration Platform, China Biomedical Literature Database, China National Knowledge Infrastructure, Chinese Scientific Journal Database (VIP), and Wan-fang database from their inception to October 2018. Only randomized controlled trials (RCTs) published in English and Chinese will be included. Continuous data will be expressed as mean difference or standard mean difference, and dichotomous data relative as risk. Study selection, data extraction, and assessment with risk of bias and data analysis will be performed by two independent authors. RevMan software version 5.3 will be used for meta-analysis. RESULTS: This study will provide high-quality evidence of ZXGD in the treatment of UA from the following aspects, including clinical efficacy, blood lipids, Seattle angina scale, electrocardiogram improvement, ST-segment depression, left ventricular ejection fraction, angina duration, and adverse events. CONCLUSION: This systematic review will provide a basis for judging whether ZXGD is an effective intervention for UA or not. PROSPERO REGISTRATION NUMBER: PROSPERO CRD 42018115528.