An integrated multi-omics analysis of topoisomerase family in pan-cancer: Friend or foe?

BACKGROUND: Topoisomerases are nuclear enzymes that get to the bottom of topological troubles related with DNA all through a range of genetic procedures. More and more studies have shown that topoisomerase-mediated DNA cleavage plays crucial roles in tumor cell death and carcinogenesis. There is however still a lack of comprehensive multi-omics studies related to topoisomerase family genes from a pan-cancer perspective. METHODS: In this study, a multiomics pan-cancer analysis of topoisomerase family genes was conducted by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from The Cancer Genome Atlas (TCGA), 481 small molecule drug response data from cancer therapeutics response portal (CTRP) as well as normal tissue data from Genotype-Tissue Expression (GTEx). Finally, overall activity-level analyses of topoisomerase in pan-cancers were performed by gene set variation analysis (GSVA), together with differential expression, clinical relevancy, immune cell infiltration and regulation of cancer-related pathways. RESULTS: Dysregulated gene expression of topoisomerase family were related to genomic changes and abnormal epigenetic modifications. The expression levels of topoisomerase family genes could significantly impact cancer progression, intratumoral heterogeneity, alterations in the immunological condition and regulation of the cancer marker-related pathways, which in turn caused the differences in potential drugs sensitivity and the distinct prognosis of patients. CONCLUSION: It was anticipated that topoisomerase family genes would become novel prognostic biomarkers for cancer patients and provide new insights for the diagnosis and treatment of tumors.

LncRNA RCAT1 promotes tumor progression and metastasis via miR-214-5p/E2F2 axis in renal cell carcinoma.

Renal cell carcinoma is the second malignant tumors in the urinary system with high mortality and morbidity. Increasing evidence suggests that long non-coding RNAs (lncRNAs) play critical roles in tumor development and progression. In the current study, based on the publicly available data obtained from GEO and TCGA database, we identified five prognosis-related lncRNAs with the ability to predict the prognosis of patients with renal cell carcinoma. Among them, the uncharacterized and upregulated lncRNA RCAT1 (renal cancer-associated transcript 1) was identified as the key lncRNA. Our data further revealed that the expression of lncRNA RCAT1 was significantly upregulated in renal cell carcinoma tissues and cells. Gain-of-function and loss-of-function studies showed that lncRNA RCAT1 promoted cell proliferation, migration, and invasion in vitro and in vivo. Furthermore, we verified that lncRNA RCAT1 could abundantly sponge miR-214-5p, which served as a tumor suppressor in renal cell carcinoma. Significantly, miR-214-5p overexpression could attenuate the promotion of cell proliferation and metastasis induced by lncRNA RCAT1. Moreover, we found that E2F2 was a direct target of miR-214-5p, and lncRNA RCAT1 could protect E2F2 from miR-214-5p-mediated degradation. Taken together, our findings suggested that lncRNA RCAT1 could enhance the malignant phenotype of renal cell carcinoma cells by modulating miR-214-5p/E2F2 axis, and lncRNA RCAT1 might be a novel prognostic biomarker and a potential therapeutic target for renal cell carcinoma.

Comparison of two detection systems for circulating tumor cells among patients with renal cell carcinoma.

BACKGROUND/AIMS: Detection of circulating tumor cells (CTCs) in cancer patients has diagnostic and prognostic importance. However, the clinical implications of CTC detection in patients with renal cell carcinoma (RCC) are still unclear. In this study, we investigated the clinical significance of CTCs using two detection systems, the CellSearch system (CSS) and isolation by size of epithelial tumor cells (ISET), among RCC patients. METHODS: We recruited 36 RCC patients and 22 healthy volunteers as controls. Blood was drawn before treatment. Samples were analyzed using the CSS and ISET. We prospectively followed the RCC patients to determine overall and progression-free survival. RESULTS: We did not detect CTCs in the control group using either the CSS or ISET. CTCs were detected in 7/36 patients (19.4%) using the CSS and in 13/36 patients (36.1%) using ISET, while circulating microemboli (CTMs) were detected in three patients (8.3%). The presence of ISET-detected CTCs correlated with clinical tumor node metastasis (TNM) stages, while the CSS-detected CTCs did not. After 36 months (median), CTCs detected by both methods failed to correlate with overall and progression-free survival among RCC patients. CONCLUSION: We discovered that ISET is more suitable than the CSS for detecting CTCs in RCC patients. The presence of CTCs/CTMs in RCC patients correlated with higher TNM stages, suggesting that the presence of CTCs could be a prognostic marker in RCC patients.

Survivin mRNA-circulating tumor cells are associated with prostate cancer metastasis.

Detection of circulating tumor cells (CTCs) has been made to develop reliable assays for early diagnosis of various cancers. Overexpression of survivin in cancer cells is strongly associated with tumor progression. Although upregulation of survivin is observed in various tumors, its expression profile in the peripheral blood of prostate cancer (PCa) patients has not yet been investigated. In this study, we validated the application of survivin as the tumor marker to detect CTC and assessed its utility for diagnosis of PCa distant metastasis. Immunohistochemistry and quantitative real-time PCR (QRT-PCR) were performed to confirm the levels of surviving expression in PCa tissues. In addition, CTC values in 3 mL of peripheral blood from PCa patients, benign prostate hyperplasia (BPH) patients, and normal controls were also measured by the survivin-targeted PCR. Our results showed that surviving was overexpressed in PCa tissues. The median levels of blood surviving mRNA of PCa patients, BPH patients, and normal controls were 5.67 (range from 0 to 12.46), 2.24 (range from 0 to 6.55), and 1.85 (range from 0 to 3.82), respectively. The levels of survivin are positively associated with PCa distant metastasis. Our results concluded that quantitation of CTCs through survivin-PCR could be a promising marker for diagnosis of PCa metastasis.

Neoadjuvant therapy combined with a BMP regimen for treating penile cancer patients with lymph node metastasis: a retrospective study in China.

BACKGROUND AND AIM: Combination chemotherapy is emerging in the management of advanced penile cancer. However, evidence-based chemotherapeutic regimens in the current guidelines are lacking. The aim of this study was to evaluate the efficacy of preoperative neoadjuvant chemotherapy combined with a BMP regimen including bleomycin (BLM), methopterin (MTX) and cisplatin (DDP) for treating advanced penile cancer patients. METHODS: We retrospectively audited the clinical and follow-up data of 24 penile cancer patients with fixed inguinal lymph node metastasis that were admitted in our hospital from 2001 to 2010 and received preoperative neoadjuvant chemotherapy. RESULTS: A total of 24 patients with advanced penile cancer (pN3) were recruited in this study. All patients received preoperative neoadjuvant chemotherapy combined with a BMP regimen. The average cycle of chemotherapy was two cycles (range 1-4 cycles). Among 24 adjuvant cases, 15 patients that responded to neoadjuvant chemotherapy underwent penectomy and inguinal lymphadenectomy. In contrast, nine cases did not respond to chemotherapy and received palliative local radiotherapy. Overall, the 1-, 2- and 5-year survival rates were 70.8, 50.0 and 45.8 %, respectively. The 5-year survival rate between the responder and non-responder groups was statistically significant (73.3 vs. 0 %, P < 0.001). CONCLUSION: Neoadjuvant chemotherapy combined with a BMP regimen followed by surgery is beneficial to patients with advanced penile cancer.