Cancer Biomarkers - Volume 28, issue 2

Authors: Wen, Ji-Feng | Jiang, Yong-Qing | Li, Chao | Dai, Xian-Kui | Wu, Tong | Yin, Wen-Zhe

Article Type: Research Article

Abstract: Chemotherapy is one of the primary treatments used against cancer. Cisplatin is a conventional chemotherapy drug used to treat osteosarcoma; however, due to the development of cisplatin resistance, advantageous therapeutic outcomes and prognosis of osteosarcoma remain low. Thus, investigation of the specific targeted therapies to circumvent the anti-chemoresistance of osteosarcoma depends on understanding the molecular mechanisms underlying cisplatin resistance. Tumor cells display an increased utilization of glycolysis rather than oxidative phosphorylation. This phenomenon is called the “Warburg effect,” which presents a survival advantage for tumor cells, leading to chemoresistance. To date, the molecular mechanism underlying osteosarcoma cisplatin resistance remains to …be fully elucidated. In this study, we reported the significant down-regulation of the long noncoding RNA-Suppressing Androgen Receptor in Renal Cell Carcinoma (lncRNA-SARCC) in the cells of osteosarcoma and in the specimens from osteosarcoma patients. Moreover, we observed a negative correlation between the lncRNA-SARCC and cisplatin resistance in the osteosarcoma tissues. Overexpression of the lncRNA-SARCC sensitizes osteosarcoma cells to cisplatin. From microarray analysis, we screened several miRNAs, which are significantly regulated by the lncRNA-SARCC in osteosarcoma cells, and revealed that lncRNA-SARCC promoted microRNA-43 (miR-143) expression in osteosarcoma. Interestingly, miR-143 showed the same expression pattern with the lncRNA-SARCC in osteosarcoma patient specimens. By establishing a cisplatin-resistant cell line from Sarcoma Osteogenic-2 (Saos-2), we found the cisplatin-resistant cells with down-regulated expressions of the lncRNA-SARCC and miR-143, but with a higher glycolysis rate compared to that in parental cells. We identified the glycolysis key enzyme, Hexokinase 2 (HK2), as a direct target for miR-143 in osteosarcoma. Restoration of the HK2 expression in the lncRNA-SARCC-overexpressing osteosarcoma cells reversed cisplatin resistance, suggesting that lncRNA-SARCC-mediated cisplatin sensitivity may be via glycolysis in the miR-143-inhibited osteosarcoma cells. Finally, results from both in vitro and in vivo xenograft models demonstrated that the lncRNA-SARCC was an effective therapeutic agent for overcoming cisplatin resistance in osteosarcoma. Our findings suggest an essential axis of the lncRNA-SARCC-miR-143-HK2 in regulation of osteosarcoma chemosensitivity, presenting the lncRNA-SARCC as a new therapeutic target against cisplatin-resistant osteosarcoma. Show more

Keywords: lncRNA-SARCC, microRNA-143, cisplatin resistance, osteosarcoma, the Warburg effect

DOI: 10.3233/CBM-191181

Citation: Cancer Biomarkers, vol. 28, no. 2, pp. 231-246, 2020

Authors: Lv, Jingjing | Zhang, Haitao | Gao, Zhimei | Zhang, Xinyan | Huang, Xin | Jia, Xiaojuan

Article Type: Research Article

Abstract: BACKGROUND: Gastric cancer is a prevalent malignant around the world. Aberrantly expression of microRNAs (miRNAs) contributes to the progression of tumors. The aim of this study was to investigate the expression and role of miR-892a in gastric cancer. METHODS: A total of 119 gastric cancer patients were enrolled in this study. And the expression of miR-892a in gastric cancer tissues and cells was measured using RT-qPCR analysis. Kaplan-Meier plotter and multivariate Cox regression analysis were used to explore the prognostic value of miR-892a in gastric cancer. The biological function of miR-892a in gastric cancer cells was …evaluated using CCK-8 assays and Transwell assays. RESULTS: The expression of miR-892a was high-expressed in gastric cancer tissues and cells. The miR-892a expression was associated with tumor size, differentiation, lymph node metastasis, and TNM stages. Gastric cancer patients with high miR-892a expression showed a short overall survival rate. Overexpression of miR-892a promoted cell proliferation, migration, and invasion of gastric cancer cells. CONCLUSION: miR-892a was upregulated and predictor of poor prognosis in gastric cancer patients. The miR-892a in gastric cancer cells significantly promoted cell proliferative, migratory, and invasive properties. Furthermore, miR-892a may be served as a prognostic marker as well as a therapeutic target for gastric cancer. Show more

Keywords: Gastric cancer, miR-892a, migration, prognosis, proliferation, invasion

DOI: 10.3233/CBM-191323

Citation: Cancer Biomarkers, vol. 28, no. 2, pp. 247-254, 2020

Authors: Iancu, Iulia V. | Botezatu, Anca | Plesa, Adriana | Huica, Irina | Fudulu, Alina | Albulescu, Adrian | Bostan, Marinela | Mihaila, Mirela | Grancea, Camelia | Manda, Dana Alice | Dobrescu, Ruxandra | Vladoiu, Susana Vilma | Anton, Gabriela | Badiu, Corin Virgil

Article Type: Research Article

Abstract: PURPOSE: DNA methylation plays an important role in thyroid oncogenesis. The aim of this study was to investigate the connection between global and local DNA methylation status and to establish the levels of important DNA methylation regulators (TET family and DNMT1 ) in thyroid tumours: follicular adenoma-FA, papillary thyroid carcinoma-PTC (classic papillary thyroid carcinoma-cPTC and papillary thyroid carcinoma follicular variant fvPTC). METHODS: Global DNA methylation profile in thyroid tumours tissue (41 paired samples) was assessed by 5-methylcytosine and 5-hydroxymethylcytosine levels evaluation (ELISA), along with TETs and DNMT1 genes expression quantification. Also, it was …investigated for the first time TET1 and TET2 promoter’s methylation in thyroid tumours. BRAF V600E mutation and RET/PTC translocation testing were performed on all investigated samples. In vitro studies upon DNA methylation in K1 thyroid cancer cells were performed with demethylating agents (5-AzaC and vitamin C). RESULTS: TET1 and TET2 displayed a significantly reduced gene expression level in PTC, while DNMT1 gene presented a high level of expression. PTC samples presented increased levels of 5-methylcytosine and low levels of 5-hydroxymethylcytosine. 5-methylcytosine levels were associated with TET1/TET2 expression levels. TET1 gene expression was significantly lower in patients positive for BRAF mutation and with RET/PTC rearrangement. TET2 gene was found hypermethylated in thyroid carcinoma patients overall, especially in PTC-follicular variant samples (p = 0.0002), where TET2 gene expression levels were significantly reduced (p = 0.0031). Furthermore, the data indicate for all thyroid cancer patients a good sensitivity (81.08%) and specificity (86.49%) regarding the use of TET1 (p < 0.0001), and TET2 (71.79%, 64.10%, p = 0.0001) hypermethylation as biomarkers for thyroid oncogenesis. CONCLUSIONS: These results suggest that TET1/TET2 gene expression and methylation may serve as potential diagnostic tools for thyroid neoplasia. Our study showed that the methylation of TET1 increases in malignant thyroid tumours. fvPTC patients presented lower methylation levels compared to cPTC and could be a discriminatory factor between two cancer types and benign lesions. TET2 is a poorer discriminator between FA and fvPTC, but it can be useful for cPTC identification. K1-cells treated with demethylating agents showed a demethylation effect, especially upon TET2 gene. The cumulative effect of L-AA and 5-AzaC proved to have a potent combined demethylating effect on genes promoter’s activation and could open new perspectives for thyroid cancer therapy. Show more

Keywords: Papillary thyroid carcinoma, DNA methylation, TETs

DOI: 10.3233/CBM-190871

Citation: Cancer Biomarkers, vol. 28, no. 2, pp. 255-268, 2020