NRG1 regulates redox homeostasis via NRF2 in papillary thyroid cancer.

Thyroid cancer is a common endocrine cancer, of which papillary thyroid cancer (PTC) is the most common type. Neuregulin 1 (NRG1), a glycoprotein mediating cell­cell signaling, plays vital roles in cellular activities; however, its role in PTC progression remains poorly understood. In this study, we performed immunohistochemistry in 196 samples from patients and found that NRG1, a potential prognostic marker is highly expressed in PTC compared with adjacent normal tissues. Cell Counting kit­8 (CCK­8) and clone formation assays indicated that NRG1 is essential for PTC cell viability and proliferation, probably by regulating redox homeostasis, which was implied by ROS generation analysis and intracellular GSH activity assay. Western blot analysis and RT­qPCR revealed that NRG1 regulates ERK pathway and the pivotal regulator of cellular redox status, nuclear factor E2­related factor 2 (NRF2), which maintains moderate reactive oxygen species (ROS) levels through a set of antioxidant response element (ARE)­containing genes. The immunohistochemical scoring of 196 PTC samples and the analysis of the data of 490 patients from The Cancer Genome Atlas (TCGA) reveled a positive association between the expression of NRG1 and NRF2. Since the presence of NRG1 regulates redox homeostasis through NRF2, protecting PTC cells from the accumulation of ROS and ROS­induced cell death, NRG1 may thus prove to be a potential therapeutic target in the treatment of thyroid cancer.

Histone methyltransferase KMT5A gene modulates oncogenesis and lipid metabolism of papillary thyroid cancer in vitro.

KMT5A (known as PR-Set7/9, SETD8 and SET8), a member of the SET domain containing methyltransferase family specifically targeting H4K20 for methylation, has been implicated in multiple biological processes. In the present study, we identified that KMT5A was elevated in 50 pairs of papillary thyroid cancer tissue samples and in cell lines K1 and TPC-1 by qRT-PCR and western blotting, as well as by immunohistochemical staining. CCK-8 assay and flow cytometric analysis revealed that inhibition of KMT5A attenuated proliferation and induced apoptosis. Transwell assays revealed that cell migration and invasion were suppressed in KMT5A-knockdown cells. Moreover, the inhibition of KMT5A arrested the cell cycle in the G1/S phase of papillary thyroid cancer cells. The TCGA data revealed that elevated KMT5A expression was significantly correlated with extrathyroidal extension, lymph node metastasis and advanced pathological stage of papillary thyroid cancer. Furthermore, we observed that inhibition of KMT5A suppressed the expression of SREBP1, SCD, FASN and ACC, key molecules involved in lipid metabolism and decreased the level of malondialdehyde in papillary thyroid cancer cells. In conclusion, KMT5A may be a novel oncogenic factor, specifically a regulator for lipid metabolism in papillary thyroid carcinoma.

Aberrant hypermethylation of the HOXD10 gene in papillary thyroid cancer with BRAFV600E mutation.

Epigenetic abnormalities as well as genetic abnormalities may play a vital role in the tumorigenesis of papillary thyroid cancer (PTC). The present study aimed to analyze the function and methylation status of the HOXD10 gene in PTC and aimed to identify relationships between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics of PTC. A total of 152 PTC patients were enrolled in the present study. The methylation status of the HOXD10 promoter was analyzed by quantitative methylation-specific polymerase chain reaction (Q-MSP). BRAFV600E mutation status was analyzed by polymerase chain reaction (PCR) followed by DNA sequencing. HOXD10 mRNA expression level was analyzed by real-time polymerase chain reaction (RT-PCR). 5-Aza-2-deoxycytidine (5-Aza) treatment was performed in 4 PTC cell lines to observe the change in HOXD10 expression. Transwell, cell cycle and apoptosis assays were then performed in an HOXD10-overexpressing PTC cell line. Furthermore, we analyzed the associations between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics in PTC. Overexpression of HOXD10 suppressed the migration of PTC cells, and promoted cell apoptosis. Q-MSP showed that methylation levels of the HOXD10 promoter were significantly higher in PTC tissues than levels in the adjacent normal thyroid tissues (P=0.02). In addition, expression of HOXD10 was decreased in the PTC cell lines and PTC tissues compared with that noted in the adjacent normal thyroid tissues (P=0.008). However, BRAFV600E mutation was detected in 42.1% of PTC patients enrolled. In addition, the BRAF mutation status was associated with the methylation and expression level of HOXD10 in PTC. We then observed that 5-Aza treatment could revert the expression of HOXD10 in PTC cell lines. Moreover, the hypermethylation of HOXD10 was associated with invasion of the primary tumor and age >45. In conclusion, the HOXD10 gene may act as a tumor suppressor in PTC. The aberrant hypermethylation and decreased expression of the HOXD10 gene were shown in PTC patients, particularly in those with BRAFV600E mutation. The epigenetic suppression of the HOXD10 gene may play a role in the tumorigenesis of PTC, and it is a prospective biomarker for the diagnosis and prognosis of PTC.

Primary chondrosarcoma of the thyroid cartilage: Surgery-based management of a rare case.

In this study, we present a case of a 52-year-old male with a chondrosarcoma of the left lamina of the thyroid cartilage. Pre-operative evaluations detected typical calcifications and delineated the extent of the tumor. The patient underwent a total laryngectomy to ensure the complete resection of the tumor. The tumor was histopathologically found to consist of chondrocytes in a hyaline cartilage matrix. The patient's post-operative course has been successful apart from the permanent tracheostomy. Herien, we discuss the methods and rationales for the diagnosis and management of and recovery from this rare tumor, and also provide a review of the literature.

[Effects of soybean isoflavones on RAGE mediated signal transduction in the hippocampus of rats with Alzheimer's disease].

OBJECTIVE: To investigate the effects of soybean isoflavones on receptor for advanced glycation end products (RAGEs) mediated signal transduction in the hippocampus of rats with Alzheimer's disease (AD). METHODS: AD rat model was established by bilateral hippocampus injection of amyloid beta25-35 (Abeta25-35). Sixty rats were equally randomized into 5 groups, i.e., the model group, the high dose soybean isoflavones group (at the daily dose of 30 mg/kg), the low dose soybean isoflavones group (at the daily dose of 10 mg/kg), the estrogen group (at the daily dose of 0.4 mg/kg), and the sham-operation control group. Three days after modeling 2 mL soybean isoflavones or estrogen was respectively administrated to rats in the high dose soybean isoflavones group, the low dose soybean isoflavones group, and the estrogen group by gastrogavage. Equal volume of 0.5% CMC-Na was administered to rats in the model group and the sham-operation group. The treatment lasted for 21 days. The contents of RAGE and interleukin-6 (IL-6) in the hippocampus were measured by ELISA. The activity of cysteine-containing aspartate-specific protease-3 (Caspase-3) was measured by spectrophotometry. The expressions of phosphorylation extracellular signal-regulated kinase1/2 (P-ERK1/2) in the hippocampus were measured by immunohistochemical assay. RESULTS: Compared with the model group, soybean isoflavones could significantly decrease the contents of RAGE and IL-6, the activity of Caspase-3, and the phosphorylation level of ERK1/2 in the hippocampus of AD model rats (P < 0.01). CONCLUSION: Soybean isoflavones could down-regulate RAGE mediated inflammatory signal transduction in the hippocampus of AD rats, attenuate the inflammatory reactions, reduce the neurotoxicity of Abeta, and resist the apoptosis of hippocampal neurons.

[Experimental study on prevention and treatment of osteoporosis by phytoestrogen].

OBJECTIVE: To observe the effect of phytoestrogen (PE) in preventing and treating osteoporosis in ovariectomized rats. METHODS: Forty-five Wistar female rats, 3 months old, were randomly divided into the sham-operated group, the model group, low dose and high dose PE groups, and the positive control group, 9 in each group. All rats, except that those in the sham operated group were simutaneously operated, were ovariectomized. The medication started from the 31st days after operation by daily given saline per os to the sham-operated group and the model group, PE per os to the PE groups, and estradiol by intramuscular injection to the positive control group. The animals were sacrificed 90 days later, their sera were collected for determination of biochemical parameters, their right femoral bone was taken to detect the bone mineral density (BMD), left femoral bone to examine pathology of bone trabecula, and whole uterus was weighed to calculate the uterine index. RESULTS: PE could increase the BMD level, serum estradiol and inorganic phosphorus content, and uterine index, lower serum BGP, tartrate-resistant acid phosphatase (TRAP), alkaline phosphatuse (AKP) and interleukin-6 levels. Pathological examination showed that in the model group, the cortex of bone thinned, bone trabecula thinned also, with poor integrity, distorted, broken and decreased in size, while in the PE groups, the above-mentioned changes were significantly alleviated. CONCLUSION: PE is effective in preventing and treating osteoporosis in ovariectomized rats.