BackgroundOvarian cancer (OvCa) is one of the most common malignant diseases of the female reproductive system in the world. The majority of OvCa is diagnosed with metastasis in the abdominal cavity. Epithelial-to-mesenchymal transition (EMT) plays a key role in tumor cell metastasis. However, it is still unclear whether long non-coding RNA (lncRNA) is implicated in EMT and influences cell invasion and metastasis in OvCa.ResultsIn this study, using bioinformatcis analysis, we constructed a lncRNA-mediated competing endogenous RNA (ceRNA) network for mesenchymal OvCa and identified lncRNA AP000695.4, which we named pro-transition associated RNA (PTAR). PTAR was significantly up-regulated in the mesenchymal subtype samples compared with the epithelial subtype samples from the TCGA OvCa data sets. In addition, our study showed that PTAR expression was positively correlated with the expression level of ZEB1 in the mesenchymal OvCa samples. Meanwhile, we found that silencing miR-101 promoted cell migration, whereas the overexpression of miR-101 suppressed EMT and cell migration in OvCa cell lines through the regulation of ZEB1. Further analysis showed that enhanced expression of PTAR promoted EMT and metastasis through the regulation of miR-101, whereas silencing PTAR led to the attenuation of TGF-β1-induced tumorigenicity in ovarian cancer cells. Mechanistically, we found that PTAR acted as a ceRNA of miR-101, as forced expression of PTAR reduced the expression and activity of miR-101. More importantly, the knockdown of PTAR reduced tumorigenicity and metastasis in vivo.ConclusionsTaken together, the results from our study highlight a role for the PTAR-miR-101-ZEB1 axis in OvCa, which offers novel strategies for the prevention of metastasis in OvCa.

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high-lethality fibrotic lung disease characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and, ultimately, loss of lung function. Although dysregulation of some microRNAs (miRs) has been shown to play important roles in the pathophysiological processes of IPF, the role of miRs in fibrotic lung diseases is not well understood. In this study, we found downregulation of miR-26a in the lungs of mice with experimental pulmonary fibrosis and in IPF, which resulted in posttranscriptional derepression of connective tissue growth factor (CTGF), and induced collagen production. More importantly, inhibition of miR-26a in the lungs caused pulmonary fibrosis in vivo, whereas overexpression of miR-26a repressed transforming growth factor (TGF)-β1-induced fibrogenesis in MRC-5 cells and attenuated experimental pulmonary fibrosis in mice. Our study showed that miR-26a was downregulated by TGF-β1-mediated phosphorylation of Smad3. Moreover, miR-26a inhibited the nuclear translocation of p-Smad3 through directly targeting Smad4, which determines the nuclear translocation of p-Smad2/Smad3. Taken together, our experiments demonstrated the antifibrotic effects of miR-26a in fibrotic lung diseases and suggested a new strategy for the prevention and treatment of IPF using miR-26a. The current study also uncovered a novel positive feedback loop between miR-26a and p-Smad3, which is involved in pulmonary fibrosis.

BackgroundDeregulations of long non-coding RNAs (lncRNAs) have been implicated in cancer initiation and progression. Current methods can only capture differential expression of lncRNAs at the population level and ignore the heterogeneous expression of lncRNAs in individual patients.MethodsWe propose a method (LncRIndiv) to identify differentially expressed (DE) lncRNAs in individual cancer patients by exploiting the disrupted ordering of expression levels of lncRNAs in each disease sample in comparison with stable normal ordering. LncRIndiv was applied to lncRNA expression profiles of lung adenocarcinoma (LUAD). Based on the expression profile of LUAD individual-level DE lncRNAs, we used a forward selection procedure to identify prognostic signature for stage I-II LUAD patients without adjuvant therapy.ResultsIn both simulated data and real pair-wise cancer and normal sample data, LncRIndiv method showed good performance. Based on the individual-level DE lncRNAs, we developed a robust prognostic signature consisting of two lncRNA (C1orf132 and TMPO-AS1) for stage I-II LUAD patients without adjuvant therapy (P = 3.06 × 10−6, log-rank test), which was confirmed in two independent datasets of GSE50081 (P = 1.82 × 10−2, log-rank test) and GSE31210 (P = 7.43 × 10−4, log-rank test) after adjusting other clinical factors such as smoking status and stages. Pathway analysis showed that TMPO-AS1 and C1orf132 could affect the prognosis of LUAD patients through regulating cell cycle and cell adhesion.Conclusions LncRIndiv can successfully detect DE lncRNAs in individuals and be applied to identify prognostic signature for LUAD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0666-z) contains supplementary material, which is available to authorized users.

Background: Matrine is one of the major alkaloids extracted from Sophora flavescens and has been used clinically for breast cancer with notable therapeutic efficacy in China. However, the mechanisms are still largely unknown. Methods: Cell viability was analyzed by MTT assay. After MCF-7 cells were treated with matrine for 48h, apoptosis was detected by flow cytometry, TUNEL assay and transmission electron microscopy, and the cell cycle distribution was also analyzed by flow cytometry. Further, the expression of PTEN, pAkt, Akt, pBad, Bad, p21^/WAF1/CIP1 , and p27^/KIP1 was determined by Western blot. Changes of miR-21 level were quantified by real-time RT-PCR. After miR-21 was transfected in MCF-7 cells, PTEN protein level was measured by Western blot. Results: Matrine inhibited MCF-7 cell growth in a concentration-and time-dependent manner, by inducing apoptosis and cell cycle arrest at G₁/S phase. Matrine up-regulated PTEN by downregulating miR-21 which in turn dephosphorylated Akt, resulting in accumulation of Bad, p21^/WAF1/CIP1 and p27^/KIP1. Conclusion: Our study unraveled, for the first time, the ability of matrine to suppress breast cancer growth and elucidated the miR-21/PTEN/Akt pathway as a signaling mechanism for the anti-cancer action of matrine. Our findings also reinforce the notion that miRNAs can act as mediators of the therapeutic efficacy of natural medicines.

Rationale: Cardiac fibrosis is associated with various cardiovascular diseases and can eventually lead to heart failure. Dysregulation of long non-coding RNAs (lncRNAs) has recently been recognized as one of the key mechanisms involved in cardiac diseases. However, the potential roles and underlying mechanisms of lncRNAs in cardiac fibrosis have not been explicitly delineated.Methods and Results: Using a combination of in vitro and in vivo studies, we identified a lncRNA NONMMUT022555, which is designated as a pro-fibrotic lncRNA (PFL), and revealed that PFL is up-regulated in the hearts of mice in response to myocardial infarction (MI) as well as in the fibrotic cardiac fibroblasts (CFs). We found that knockdown of PFL by adenoviruses carrying shRNA attenuated cardiac interstitial fibrosis and improved ejection fraction (EF) and fractional shortening (FS) in MI mice. Further study showed that forced expression of PFL promoted proliferation, fibroblast-myofibroblast transition and fibrogenesis in mice CFs by regulating let-7d, whereas silencing PFL mitigated TGF-β1-induced myofibroblast generation and fibrogenesis. More importantly, PFL acted as a competitive endogenous RNA (ceRNA) of let-7d, as forced expression of PFL reduced the expression and activity of let-7d. Moreover, let-7d levels were decreased in the MI mice and in fibrotic CFs. Inhibition of let-7d resulted in fibrogenesis in CFs, whereas forced expression of let-7d abated fibrogenesis through targeting platelet-activating factor receptor (Ptafr). Furthermore, overexpression of let-7d by adenoviruses carrying let-7d precursor impeded cardiac fibrosis and improved cardiac function in MI mice.Conclusion: Taken together, our study elucidated the role and mechanism of PFL in cardiac fibrosis, indicating the potential role of PFL inhibition as a novel therapy for cardiac fibrosis.

Cardiac hypertrophy accompanied by maladaptive cardiac remodeling is the uppermost risk factor for the development of heart failure. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have various biological functions, and their vital role in the regulation of cardiac hypertrophy still needs to be explored. In this study, we demonstrated that lncRNA Plscr4 was upregulated in hypertrophic mice hearts and in angiotensin II (Ang II)–treated cardiomyocytes. Next, we observed that overexpression of Plscr4 attenuated Ang II-induced cardiomyocyte hypertrophy. Conversely, the inhibition of Plscr4 gave rise to cardiomyocyte hypertrophy. Furthermore, overexpression of Plscr4 attenuated TAC (transverse aortic constriction)-induced cardiac hypertrophy. Finally, we demonstrated that Plscr4 acted as an endogenous sponge of miR-214 and forced expression of Plscr4 downregulated miR-214 expression to promote Mfn2 and attenuate hypertrophy. In contrast, knockdown of Plscr4 upregulated miR-214 to induce cardiomyocyte hypertrophy. Additionally, luciferase assay showed that miR-214 was the direct target of Plscr4, and overexpression of miR-214 counteracted the anti-hypertrophy effect of Plscr4. Collectively, these findings identify Plscr4 as a negative regulator of cardiac hypertrophy in vivo and in vitro due to its regulation of the miR-214-Mfn2 axis, suggesting that Plscr4 might act as a therapeutic target for the treatment of cardiac hypertrophy and heart failure.

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