Identification of circRNA-miRNA-mRNA network regulated by Hsp90 in human melanoma A375 cells.

BACKGROUND: Melanoma is the deadliest form of skin cancer. Heat shock protein 90 (Hsp90) is highly expressed in human melanoma. Hsp90 inhibitors can suppress the growth of human melanoma A375 cells; however, the underlying mechanism remains unclear. METHODS: A375 cells were treated with SNX-2112, an Hsp90 inhibitor, for 48 h, and whole-transcriptome sequencing was performed. RESULTS: A total of 2,528 differentially expressed genes were identified, including 895 upregulated and 1,633 downregulated genes. Pathway enrichment analyses of differentially expressed mRNAs identified the extracellular matrix (ECM)-receptor interaction pathway as the most significantly enriched pathway. The ECM receptor family mainly comprises integrins (ITGs) and collagens (COLs), wherein ITGs function as the major cell receptors for COLs. 19 upregulated miRNAs were found to interact with 6 downregulated ITG genes and 8 upregulated miRNAs were found to interact with 3 downregulated COL genes. 9 differentially expressed circRNAs in SNX-2112-treated A375 cells were identified as targets of the ITG- and COL-related miRNAs. Based on the differentially expressed circRNAs, miRNAs, and mRNAs, ITGs- and COL-based circRNA-miRNA-mRNA regulatory networks were mapped, revealing a novel regulatory mechanism of Hsp90-regulated melanoma. CONCLUSION: Targeting the ITG-COL network is a promising approach to the treatment of melanoma.

Application of Nano-Carbon Tracing Technology in Thyroid Cancer and Its Relationship with Cytotoxic T Lymphocyte Antigen 4 Gene Polymorphism.

The most common malignant tumor of the human endocrine system is thyroid cancer, most used surgical treatment for thyroid cancer is total thyroidectomy with central lymph node dissection. However, surgery and thorough lymph node dissection can easily damage the parathyroid glands and cause corresponding surgery. Symptoms such as permanent hyperparathyroidism, nano-carbon is a common type of new lymphoid tissue tracer, it is mainly used to trace lymphoid tissue in tumor surgery. With the continuous advancement of surgical technology, more and more scholars have used nano-carbon to trace lymphoid tissue during thyroid cancer surgery, and have achieved good results. The results of this study show that thyroid cancer surgery with nano-carbon to negatively develop the parathyroid glands significantly reduces the incidence of serum PTH and blood calcium decline, and largely protects the parathyroid glands. Practice has also shown that the use of nano-carbon tracers is more thorough in lymph node dissection than thyroid cancer surgery without nano-carbon tracers.

Promoter hypermethylation of the CFTR gene as a novel diagnostic and prognostic marker of breast cancer.

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths among women. New biomarkers with definite diagnostic and prognostic efficacy are urgently needed. Here, we showed that the promoter of the cystic fibrosis transmembrane conductance regulator (CFTR) was hypermethylated in breast cancer. The messenger RNA level of CFTR was downregulated in breast cancer. Notably, all 19 breast cancer patients with hypermethylated CFTR were diagnosed with invasive carcinoma. Moreover, CFTR was upregulated in decitabine (10 µM) treated breast cancer cells. Overexpression of CFTR inhibited cell growth whereas knockdown of CFTR promoted cell invasion. In the tissue array analysis, the CFTR protein level decreased significantly in breast cancer and low CFTR protein level correlated with poor survival with a P-value of 0.034. Thus, promoter hypermethylation of the CFTR gene might be a novel diagnostic marker of breast cancer.

The Transareola Endoscopic Approach Yields Adequate Oncological Dissection as Open Approach in the Treatment of Papillary Thyroid Carcinoma.

OBJECTIVE: This study aimed to evaluate and discuss whether the transareola endoscopic surgery has similar outcome outcomes to open surgery in the treatment of papillary thyroid carcinoma (PTC). METHOD: A total of 102 patients with PTC were enrolled in this study. Among them, 53 patients were treated by transareola endoscopic surgery (endoscopic group) and 49 patients were treated by open surgery (open group). Some specific factors, including thyroglobulin (Tg), radioactive iodine uptake (RAIU), postoperative nuclide imaging in thyroid area, postoperative nuclide imaging of lymph nodes suspicious for metastasis (PNILNSM), etc. were analyzed and compared between the 2 groups. RESULTS: There were no significant differences between the 2 groups regarding body mass index (22.9±3.4 vs. 24.0±3.3, P=0.103), operation time (173.3±43.2 vs. 158.8±47.9 min, P=0.110), intraoperative blood loss (41.8±19.4 vs. 35.8±31.0 mL, P=0.251, P=0.251), tumor diameter (19.0±6.8 vs. 20.2±7.2 mm, P=0.400), and overall complications (11.3% vs. 10.2%, P=0.868). No significant difference was found in the specific factors between the 2 groups concerning RAIU-2h/24h (2.44±1.34 vs. 2.58±1.65%/2.83±3.75 vs. 2.35±3.44%, P=0.646/ P=0.506), number of dissected lymph nodes (4.4±1.4 vs. 4.6±1.5, P=0.595), Tg before radioiodine therapy (4.46±5.50 vs. 5.60±8.36; P=0.495), Tg after radioiodine therapy (1.03±1.93 vs. 1.11±1.61, P=0.812, P=0.812), postoperative nuclide imaging in thyroid area (1.76±1.50 vs. 2.19±1.85 cm, P=0.195), PNILNSM before radioiodine (none: 79.2% vs. 83.7%, P=0.566; central: 17.0% vs. 12.2%, P=0.653; lateral: 1.9% vs. 4.1%, P=0.450; central+lateral: 1.9% vs. 0%, P=1.000), and PNILNSM after radioiodine (none: 94.3% vs. 95.9%, P=0.111; central: 3.8% vs. 2.0%, P=1.000; lateral: 0 vs. 2.0%, P=0.480; central+lateral: 1.9% vs. 0%, P=1.000). CONCLUSIONS: Transareola endoscopic total thyroidectomy and central lymph nodes dissection are safe and effective. According to the evaluated postoperative specific factors, this technique achieves similar outcomes to open surgery in selected patients with PTC.

JQ1, a BET-bromodomain inhibitor, inhibits human cancer growth and suppresses PD-L1 expression.

Most traditional cytotoxic chemotherapeutic agents have poor aqueous solubility and significant toxicity. Hence, there is a need to develop molecule-targeted drugs. Programmed death-ligand 1 (PD-L1) is associated with the prognosis of several cancer types, and blockade of PD-1/PD-L1 signaling increases the amplitude of anti-tumor immunity. In the present study, we investigated the effects of JQ1, a bromodomain and extraterminal-bromodomain inhibitor, on cell growth, and messenger RNA (mRNA) and protein levels of PD-L1 in renal cell carcinoma primary culture cells, and prostate, liver, and lung cancer cell lines. The results of the cell counting kit-8 assay suggested that JQ1 inhibits cell growth in a dose-dependent manner. The mRNA and protein levels of PD-L1 decreased in the primary culture of JQ1-treated renal carcinoma, prostate cancer, liver cancer, and lung cancer cell lines. In addition, the mRNA level of PD-L2 also decreased in the JQ1-treated cells. Overall, JQ1 might be a potential anti-tumor agent.

Mitochondrial targeting of TR3 is involved in TPA induced apoptosis in breast cancer cells.

TPA is considered to be a tumor promoting molecule that induces the expression of COX-2 protein. However, it is contradictory to find that TPA can induce tumor cell apoptosis and exert antitumor activity. Therefore, the role of TPA in tumorigenesis and development has not yet been elucidated. Here we show that TPA can promote the apoptosis of breast cancer cells and increase the ratio of Bax/Bcl-2. It is suggested that TPA may induce apoptosis of breast cancer cells through mitochondrial apoptosis pathway. Further studies showed that TPA could cause mitochondrial dysfunction and trigger mitochondrial apoptotic pathway. In mechanism, the mitochondrial targeting of TR3 is involved in TPA induced apoptosis in breast cancer cells. In conclusion, our findings suggest that TPA can play a role in inhibiting cancer by inducing apoptosis and TR3 is expected to be a new target for cancer treatment.

BJ-B11, an Hsp90 Inhibitor, Constrains the Proliferation and Invasion of Breast Cancer Cells.

Breast cancer is the leading cause of cancer-related deaths in women; however, its underlying etiology remains largely unknown. In this study, we systematically analyzed breast cancer tissues using comprehensive iTRAQ labeled quantitative proteomics, identifying 841 differentially expressed proteins (474 and 367 significantly over- and under-expressed, respectively), which were annotated by protein domain analysis. All the heat shock proteins identified were upregulated in breast cancer tissues; Hsp90 upregulation was also validated by RT-qPCR and immunohistochemistry, and high Hsp90 protein levels correlated with poorer survival. Hsp90AA1 overexpression promoted MDA-MB-231 cell proliferation, whilst BJ-B11, an Hsp90 inhibitor, hampered their invasion, migration, and proliferation in a time and dose-dependent manner and induced cell cycle arrest and apoptosis. BJ-B11 inhibited the expression of epithelial-mesenchymal transition (EMT) marker in MDA-MB-231 cells, whereas Hsp90AA1 promoted its expression. Moreover, BJ-B11 inhibited tumor growth in xenograft model. Altogether, Hsp90 activation is a risk factor in breast cancer patients, and BJ-B11 could be used to treat breast cancer.

LncRNA FOXD2-AS1 accelerates the papillary thyroid cancer progression through regulating the miR-485-5p/KLK7 axis.

It has been proved that long noncoding RNAs (lncRNAs) are important modulators in the tumorigenesis and progression of various malignant tumors. Recently, lncRNA FOXD2-AS1 has been reported to be an oncogene in several kinds of human cancers. However, the function of FOXD2-AS1 in papillary thyroid cancer (PTC) has not been well investigated. This study aims to explore the biological role and mechanism of FOXD2-AS1 in PTC. At first, the expression of FOXD2-AS1 was examined in PTC tissues and cell lines with quantitative reverse transcription-polymerase chain reaction (qRT-PCR). FOXD2-AS1 was found to observably upregulated in PTC tissues and cell lines. Kaplan-Meier survival analysis revealed that high expression of FOXD2-AS1 was closely correlated with the unfavorable prognosis of patients with PTC. Based on the TCGA data set, KLK7 was overexpressed in PTC tumor samples. Our experimental data further validated the upregulation of KLK7 in PTC tissues and cell lines. Similarly, high level of KLKF was associated with poor prognosis of patients with PTC. The positive expression association between FOXD2-AS1 and KLK7 was analyzed with Pearson correlation coefficient. Loss-of-function assays revealed that knockdown of FOXD2-AS1 or KLK7 greatly inhibited PTC cell proliferation and migration, while induced cell apoptosis. Results of mechanism experiments suggested that FOXD2-AS1 functioned as a competing endogenous RNA (ceRNA) to enhance the expression of KLK7 by sponging miR-485-5p in PTC. Rescue assays were conducted to verify the function of FOXD2-AS1/miR-485-5p/KLK7 axis in PTC progression.