Up-regulation of mir-10b predicate advanced clinicopathological features and liver metastasis in colorectal cancer

Abstract

Given the emerging role of microRNA in tumor disease progression, we investigated the association between miRNA 10b expression, liver metastasis, and clinicopathological of colorectal cancer (CRC). Two hundred and forty-six pairs of samples (including CRC samples and normal adjacent tissues) from CRC patients were collected from May 2004 to May 2009. All samples verified to contain at least 80% tumor cells, and were immediately frozen in liquid nitrogen and stored at −80°C or fixed in 10% formalin for paraffin embedding. The expression of miRNA-10b in CRC tissues was evaluated using a quantitative real-time polymerase chain reaction RT-PCR. Correlation between miR-10b expression and poor clinicopathological of CRC patients were analyzed using Student's t-tests and Chi-square tests. A Kaplan–Meier survival curve was generated following a log-rank test. miR-10b expression was up-regulated in CRC tissues (P < 0.0001) and in patients diagnosed as colorectal liver metastasis (CLM) at initial involvement or during follow-up. When the Tumor Node Metastasis (TNM) stage was taken into consideration, the expression levels of miR-10b were positively correlated with advanced TNM stages. In addition, the miR-10b expression of patients diagnosed as CLM at initial involvement was significantly higher than those without liver metastasis (nCLM). Similarly, those patients developed with CLM during follow-up (FCLM) was also markedly higher than those with nCLM. miR-10b expression was also found correlated with advanced stage (P < 0.0001), lymph node metastasis (P = 0.025), venous infiltration (P = 0.007), poorer differentiation (P = 0.002), and served as an independent prognostic factor of poor overall survival (P < 0.0001). This study demonstrated the expression of miR-10b had strong potential to serve as a noninvasive biomarker for CRC prognosis and predicting liver metastasis.

miR-10b expression was also found correlated with advanced stage (P < 0.0001), lymph node metastasis (P = 0.025), venous infiltration (P = 0.007), poorer differentiation (P = 0.002), and served as an independent prognostic factor of poor overall survival (P < 0.0001).

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Cause-specific mortality in women with breast cancer in situ

Abstract

The long-term mortality remains unknown in women diagnosed with breast cancer in situ (BCIS). Here we assessed the cause-specific mortality in BCIS patients. This population-based cohort study included 12 243 women diagnosed with BCIS in Sweden between 1980 and 2011. Patients were followed until death, emigration, or 31 December 2013, whichever came first. The 30-year cumulative incidence of breast cancer-specific mortality was 6.3%, which is considerably lower than 49.7% observed for other-cause mortality. Women diagnosed with BCIS were more likely to die from breast cancer (standardize mortality ratio [SMR], 3.85; 95%CI, 3.47-4.27) but less likely to die from cardiovascular disease (SMR, 0.88; 95% CI, 0.82-0.95) than women in the general population. Specifically, the SMRs for breast cancer-specific mortality decreased over time from 5.17 (95%CI, 3.95-6.81) among BCIS diagnosed during 1980-1989 to 3.03 (95%CI, 2.35-3.91) among those diagnosed during 2000-2011. Furthermore, higher risk of death from other causes was seen among those with older age at BCIS diagnosis, lower levels of education, nulliparity, higher Charlson Comorbidity Index, and being hospitalized before BCIS diagnosis; whereas lower risk of death from breast cancer was seen among BCIS diagnosed in the later time period and those with younger age at first birth. We conclude that most women diagnosed with BCIS die from causes other than breast cancer, which highlights the need for actions not only to reduce non-breast cancer mortality but also to identify patient where extensive curative BCIS treatment is not adding to survival. This article is protected by copyright. All rights reserved.

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EZH2 Coupled with HOTAIR to Silence MicroRNA-34a by the induction of heterochromatin formation in Human Pancreatic Ductal Adenocarcinoma

Abstract

MicroRNA-34a (miR-34a) is frequently downregulated in pancreatic ductal adenocarcinoma (PDAC) cells, however, the silencing mechanism remains unclear. Enhancer of zeste homolog 2 (EZH2) is overexpressed in PDAC, and our previous miRNA profiling showed that inhibition of EZH2 in PDAC cells led to the re-expression of a group of tumor suppressor miRNAs including miR-34a. Here, we studied the effect of ectopic EZH2 expression to the silencing of miR-34a, and identified HOTAIR as an interacting partner to induce heterochromatin formation during miR-34a repression.

We identified EZH2 as a major player in silencing miR-34a. Inhibition of EZH2 upregulated miR-34a expression in PDAC cells, while EZH2 overexpression in human pancreatic ductal epithelial (HPDE) cells repressed miR-34a expression and decreased the miR-34a promoter activity. We then showed that HOTAIR played a critical role in EZH2-mediated repression of miR-34a, as knockdown of HOTAIR attenuated the miR-34a inhibition effect in EZH2-overexpressing HPDE cells. HOTAIR physically interacted with miR-34a promoter, and the EZH2-interacting region located at 5' HOTAIR RNA was essential in repressing miR-34a and promoting cell proliferation. More importantly, we showed that the interaction between EZH2 and HOTAIR underlay the silencing of miR-34a through induction of heterochromatin formation. We first showed that manipulation of EZH2 level interfered the occupancy of heterochromatin markers H3K9me2, heterochromatin associated protein 1α and 1γ in PDAC cells. In turn, we showed that knockdown of HOTAIR reduced the occupancy of EZH2 at miR-34a promoter. The identification of HOTAIR-guided miR-34a silencing opened a new avenue in miR-34a-oriented therapy against PDAC. This article is protected by copyright. All rights reserved.

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Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts

Abstract

It has recently been reported that a large proportion of human malignant pleural mesothelioma (MPM) cell lines and patient tissue samples present high expression of the c-MYC oncogene. This gene drives several tumorigenic processes and is overexpressed in many cancers. Although c-MYC is a strategic target to restrain cancer processes, no drugs acting as c-MYC inhibitors are available. The novel thienotriazolodiazepine small-molecule bromodomain inhibitor OTX015/MK-8628 has shown potent antiproliferative activity accompanied by c-MYC downregulation in several tumor types. This study was designed to evaluate the growth inhibitory effect of OTX015 on patient-derived MPM473, MPM487 and MPM60 mesothelioma cell lines and its antitumor activity in three patient-derived xenograft models, MPM473, MPM487 and MPM484, comparing it with cisplatin, gemcitabine and pemetrexed, three agents which are currently used to treat MPM in the clinic. OTX015 caused a significant delay in cell growth both in vitro and in vivo. It was the most effective drug in MPM473 xenografts and showed a similar level of activity as the most efficient treatment in the other two MPM models (gemcitabine in MPM487 and cisplatin in MPM484). In vitro studies showed that OTX015 downregulated c-MYC protein levels in both MPM473 and MPM487 cell lines. Our findings represent the first evidence of promising therapeutic activity of OTX015 in mesothelioma. This article is protected by copyright. All rights reserved.

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TCGA Data Leveraged for Developing FDA-Designated Breakthrough Therapy

LOXO-101, a promising new drug developed by Loxo Oncology, received FDA breakthrough therapy designation in July, 2016, for the treatment of metastatic cancers with tropomyosin receptor kinase (TRK) fusions. Using publically available data, including those from The Cancer Genome Atlas (TCGA), Loxo Oncology identified TRK fusions as prime targets for drug development, says Loxo Oncology's Chief Executive Officer, Josh Bilenker, M.D.

"We found that TCGA efforts had contributed to a better understanding of the clinical settings in which TRK fusions occur. Also, TCGA data helped confirm that TRK fusions were typically present in the absence of other known oncogenic drivers," said Dr. Bilenker. "Taken together, these insights helped point the way to clinical settings we might not have considered, while increasing our confidence that TRK fusions were likely to be oncogenic drivers susceptible to therapeutic intervention."

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Letter to the editor regarding the paper by A. Lozano-Blázquez et al. Differences in cancer drug assessment between Spain and the United Kingdom

Publication date: November 2016
Source:European Journal of Cancer, Volume 67
Author(s): Alba Prat, Antoni Gilabert, Ruth Puig-Peiro, Anna Feliu, Mireia Riba, Maria Antonia Mangues, Josep Tabernero




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