miR-665 expression predicts poor survival and promotes tumor metastasis by targeting NR4A3 in breast cancer.

Cancer metastasis is the main cause of death in breast cancer (BC) patients. Therefore, prediction and treatment of metastasis is critical for enhancing the survival of BC patients. In this study, we aimed to identify biomarkers that can predict metastasis of BC and elucidate the underlying mechanism of the functional involvement of such markers in metastasis. miRNA expression profile was analyzed using a custom microarray system in 422 BC tissues. The relationship between the upregulated miR-665, metastasis and survival of BC was analyzed and verified in another set of 161 BC samples. The biological function of miR-665 in BC carcinogenesis was explored with in vitro and in vivo methods. The target gene of miR-665 and its signaling cascade were also analyzed. There are 399 differentially expressed miRNAs between BC and noncancerous tissues, of which miR-665 is the most upregulated miRNA in the BC tissues compared with non-tumor breast tissues (P < 0.001). The expression of miR-665 predicts metastasis and poor survival in 422 BC patients, which is verified in another 161 BC patients and 2323 BC cases from online databases. Ectopic miR-665 expression promotes epithelial-mesenchymal transition (EMT), proliferation, migration and invasion of BC cells, and increases tumor growth and metastasis of BC in mice. Bioinformatics, luciferase assay and other methods showed that nuclear receptor subfamily 4 group A member 3 (NR4A3) is a target of miR-665 in BC. Mechanistically, we demonstrated that miR-665 promotes EMT, invasion and metastasis of BC via inhibiting NR4A3 to activate MAPK/ERK kinase (MEK) signaling pathway. Our study demonstrates that miR-665 upregulation is associated with metastasis and poor survival in BC patients, and mechanistically, miR-665 enhances progression of BC via NR4A3/MEK signaling pathway. This study provides a new potential prognostic biomarker and therapeutic target for BC patients.

Identification of microRNA-615-3p as a novel tumor suppressor in non-small cell lung cancer.

Lung cancer is the most frequent cause of mortality in cancer patients; non-small-cell lung cancer (NSCLC) accounts for ~80% of lung cancer cases. MicroRNAs (miRNAs) have been revealed to perform an important role in cancer development and progression. Based on a custom miRNA microarray analysis of patients with NSCLC, miRNA-615-3p (miR-615-3p) downregulation was identified in NSCLC tissues compared with normal lung tissues, which suggested that miR-615-3p acted as a tumor suppressor in lung cancer. The overexpression of miR-615-3p was then validated using 40 pairs of NSCLC and adjacent normal tissue samples using a TaqMan reverse transcription-quantitative polymerase chain reaction assay. In order to investigate the tumor suppressor function of miR-615-3p, the ectopic expression of miR-615-3p in the NSCLC A549, H1299 and H1650 cell lines was established. The results revealed that overexpressed miR-615-3p markedly inhibited cell proliferation and colony formation in the 3 NSCLC cell lines compared with the cells overexpressing the negative control sequence (NC). Additional investigation revealed that miR-615-3p overexpression significantly induced apoptosis and cell cycle arrest at the G1 phase in the A549, H1299 and H1650 cell lines compared with the cells overexpressing NC. Finally, ectopic expression of miR-615-3p was found to repress the cell migration and invasion of the 3 lung cancer cell lines. The results of the present study demonstrate, for the first time, that miR-615-3p functions as a tumor suppressor in NSCLC, and may be a novel potential molecular therapeutic target for patients with NSCLC.

CT-diagnosed severe skull base bone destruction predicts distant bone metastasis in early N-stage nasopharyngeal carcinoma.

Bone metastasis is the most frequent type of distant metastasis in nasopharyngeal carcinoma (NPC). In this study, we investigated the correlation between the skull base bone destruction and the distant bone metastasis in patients with NPC. A total of 449 cases with NPC who were diagnosed and had definitive radiotherapy from 2001 to 2006 were enrolled in this study. The skull base bone destruction was diagnosed by computed tomography (CT) in all cases, and 191 patients also underwent magnetic resonance imaging scan. Kaplan-Meier method was adopted to perform the univariate analysis; Cox regression model was used to perform multivariate analysis to determine whether the skull base bone destruction when diagnosed by CT was an independent impact factor of the distant bone metastases. The group with skull base bone destruction had a distant bone metastases rate of 9.0% (14/155), whereas the group without skull base bone destruction had rate of 4.1% (12/294). The multivariate analysis showed that the skull base bone destruction, when diagnosed by CT, was an independent impact factor of the distant bone metastases-free survival in the early N-staging cases, but was not an independent impact factor when diagnosed by MRI. The skull base bone destruction diagnosed by CT in patients with NPC had predictive value for the distant bone metastases, especially for the early N-staging cases.

miR-601 is a prognostic marker and suppresses cell growth and invasion by targeting PTP4A1 in breast cancer.

MicroRNAs (miRNA) play important roles in the initiation and progression of breast cancer. Here, we investigated the role of miR-601 in breast cancer and found that its expression was significantly down-regulated in breast cancer tissues compared with matched adjacent non-cancerous breast tissues. Moreover, we found that down-regulation of miR-601 was closely associated with distant metastasis and poor distant metastasis-free survival in breast cancer. In addition, miR-601 levels were inversely correlated with metastatic potential of human breast cancer cell lines. Further experiments showed that ectopic overexpression of miR-601 suppressed breast cancer cell proliferation, migration and invasion, whereas miR-601 knockdown promoted breast cancer cell proliferation, migration and invasion. Furthermore, protein tyrosine phosphatase type IVA 1 (PTP4A1) was identified as a direct target of miR-601. Overexpression of miR-601 repressed PTP4A1 mRNA and protein expression. Conversely, inhibition of miR-601 increased PTP4A1 mRNA and protein expression. Taken together, our data suggest that miR-601 inhibits growth and invasion of breast cancer cells by targeting PTP4A1 and that miR-601 is a potential biomarker for prognosis and therapeutic target in breast cancer.

MicroRNA-711 is a prognostic factor for poor overall survival and has an oncogenic role in breast cancer.

MicroRNAs are important in cancer development and progression. In the present study, the clinical significance and function of microRNA-711 (miR-711) expression in breast cancer were investigated. The expression level of miR-711 was analyzed in breast cancer tissue samples using reverse transcription-quantitative polymerase chain reaction. Cell proliferation, colony formation, apoptosis and Transwell assays were performed in breast cancer cell lines transfected with miR-711 mimics or inhibitors, or control sequence. miR-711 was found to be upregulated in 30 formalin-fixed paraffin-embedded breast cancer tissue samples compared with paired non-cancerous breast tissues (P<0.05). Furthermore, a higher miR-711 expression was demonstrated to be associated with poor overall and disease-free survival times in 161 breast cancer patients, and miR-711 was identified as an independent prognostic factor using multivariate Cox regression analysis. In vitro, overexpression of miR-711 resulted in a significant increase in proliferation, colony formation, migration and invasion of breast cancer cells. By contrast, downregulating miR-711 inhibited cell proliferation, colony formation, migration and invasion and enhanced the rate of apoptosis of breast cancer cells. To the best of our knowledge, the present study is the first to demonstrate that miR-711 is an independent prognostic factor and serves an important oncogenic function in breast cancer, suggesting that miR-711 is a potential biomarker of prognosis and a molecular therapeutic target in breast cancer.

Continuous fall in hemoglobin level is a poor prognostic factor in patients with nasopharyngeal carcinoma treated with radiotherapy.

BACKGROUND AND OBJECTIVE: Anemia can not only reduce the quality of life of patients with cancer, but also affect their survival. This study was to investigate the prognostic value of hemoglobin (Hb) level in patients with nasopharyngeal carcinoma (NPC) treated with radiotherapy. METHODS: Clinical data of 520 NPC patients received definitive radiotherapy between 2000 and 2002 at Sun Yat sen University Cancer Center were analyzed. Patients were stratified into normal Hb level and anemia groups according to their Hb levels before, during, and after radiation. Anemia was defined according to World Health Organization criteria as Hb level < 130 g/L in men and < 120 g/L in women. Hb continuous decrease group and non decrease group were defined according to Hb changes in the patients during radiotherapy. Loco regional recurrence free survival (LRFS) and overall survival (OS) rates were estimated using the Kaplan Meier method. Multivariate analysis was performed using the Cox model to analyze the prognostic factors. RESULTS: Before radiation, the 5 year LRFS rates were 60.9% in anemia group and 63.9% in normal Hb level group (P = 0.337); the 5 year OS rates were 65.2% and 71.0%, respectively (P = 0.299). During radiation, the 5 year LRFS rates were 56.7% in anemia group and 67.9% in normal Hb level group (P = 0.013); the 5 year OS rates were 61.0% and 75.9%, respectively (P = 0.001). After radiation, the 5 year LRFS rates were 59.6% in anemia group and 64.9% in normal Hb level group (P = 0.169); the 5 year OS rates were 65.0% and 71.9%, respectively (P = 0.090). The 5 year LRFS and OS rates were significantly lower in Hb continuous decrease group than in Hb non decrease group (59.1% vs. 69.3%, P = 0.032; 66.2% vs. 76.4%, P=0.011). Multivariate analysis showed that the continuous decrease of Hb was an independent prognostic factor for OS. CONCLUSION: The change in Hb level during radiotherapy is an important prognostic factor affecting the OS of NPC patients.

[Impact of pretherapy body mass index on prognosis of nasopharyngeal carcinoma].

BACKGROUND AND OBJECTIVE: Given the limited information regarding the impact of BMI on treatment outcomes for nasopharyngeal carcinoma, we sought to examine the relationship between body mass index (BMI) and cancer control after radiotherapy. METHODS: We compared clinic outcome information across BMI groups from 1,489 patients treated with radiotherapy between 1990 and 2003. Multivariate analysis was used to determine if BMI significantly predicted adverse recurrence. RESULTS: In comparison with normal group, there were statistical difference in age, T staging, N staging, and clinical staging (P<0.0001). In survival analysis, in comparison with under-weight group, we could found the hazard ratio was less than one, in the risk of death, cancer recurrence and local recurrence. Meanwhile, the hazard ratio gradually declined when the body weight increased. In univariate survival analysis, under-weight patient had a significant decrease in overall survival,(P<0.0001). When Cox regression model was applied to multivariate analysis, we could found age, T staging, N staging, and BMI grades could be a significant independent prognosis factors(P<0.05). CONCLUSION: Under-weight patients had a significant decrease in overall survival rate, distant metastasis failure-free survival, and local relapse-free survival. Pretherapy BMI grades could be a significant independent prognosis factors.