MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

Calcium ions (Ca2+) are some of the most versatile signalling molecules, and they have many physiological functions, prominently including muscle contraction, neuronal excitability, cell migration and cell growth. By sequestering and releasing Ca2+, mitochondria serve as important regulators of cellular Ca2+. Mitochondrial Ca2+ also has other important functions, such as regulation of mitochondrial metabolism, ATP production and cell death. In recent years, identification of the molecular machinery regulating mitochondrial Ca2+ accumulation and efflux has expanded the number of (patho)physiological conditions that rely on mitochondrial Ca2+ homeostasis. Thus, expanding the understanding of the mechanisms of mitochondrial Ca2+ regulation and function in different cell types is an important task in biomedical research, which offers the possibility of targeting mitochondrial Ca2+ machinery for the treatment of several disorders.

The machineries, regulation and cellular functions of mitochondrial calcium.

Sepsis is characterized as an uncontrolled host response to infection, and it represents a serious health challenge, causing excess mortality and morbidity worldwide. The discovery of sepsis-related epigenetic and molecular mechanisms could result in improved diagnostic and therapeutic approaches, leading to a reduced overall risk for affected patients. Accumulating data show that microRNAs, non-coding RNAs, and exosomes could all be considered as novel diagnostic markers for sepsis patients. These biomarkers have been demonstrated to be involved in regulation of sepsis pathophysiology. However, epigenetic modifications have not yet been widely reported in actual clinical settings, and further investigation is required to determine their importance in intensive care patients. Further studies should be carried out to explore tissue-specific or organ-specific epigenetic RNA-based biomarkers and their therapeutic potential in sepsis patients.

Non-coding RNAs and Exosomes: Their Role in the Pathogenesis of Sepsis.

tRNA are post-transcriptionally modified by chemical modifications that affect all aspects of tRNA biology. An increasing number of mutations underlying human genetic diseases map to genes encoding for tRNA modification enzymes. However, our knowledge on human tRNA-modification genes remains fragmentary and the most comprehensive RNA modification database currently contains information on approximately 20% of human cytosolic tRNAs, primarily based on biochemical studies. Recent high-throughput methods such as DM-tRNA-seq now allow annotation of a majority of tRNAs for six specific base modifications. Furthermore, we identified large gaps in knowledge when we predicted all cytosolic and mitochondrial human tRNA modification genes. Only 48% of the candidate cytosolic tRNA modification enzymes have been experimentally validated in mammals (either directly or in a heterologous system). Approximately 23% of the modification genes (cytosolic and mitochondrial combined) remain unknown. We discuss these 'unidentified enzymes' cases in detail and propose candidates whenever possible. Finally, tissue-specific expression analysis shows that modification genes are highly expressed in proliferative tissues like testis and transformed cells, but scarcely in differentiated tissues, with the exception of the cerebellum. Our work provides a comprehensive up to date compilation of human tRNA modifications and their enzymes that can be used as a resource for further studies.

Matching tRNA modifications in humans to their known and predicted enzymes

HOTAIR LncRNA: A novel oncogenic propellant in human cancer.

// Guanghui Hu 1 * , Binbin Dong 2, * , Jingwei Zhang 1, * , Wei Zhai 1, 3 , Tiancheng Xie 1 , Bisheng Huang 1 , Chi Huang 4 , Xudong Yao 1 , Junhua Zheng 1 , Jianping Che 1, 4 and Yun-Fei Xu 1 1 Department of Urology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China 2 Department of Urology, Yancheng Third People’s Hospital, Yancheng, Jiangsu, China 3 Department of Urology, Renji Hospital, Shanghai Jiaotong University, Shanghai, China 4 Department of Urology, Shanghai Tenth People’s Hospital, Nanjing Medical University, Nanjing, Jiangsu, China * These authors have contributed equally to this work Correspondence to: Yun-Fei Xu, email: xuyunfeibb@sina.com Jianping Che, email: chejianping77@126.com Wei Zhai, email: jacky_zw2002@hotmail.com Keywords: renal cell carcinoma, HOTAIR, hippo pathway, SAV1 Received: December 31, 2016     Accepted: March 14, 2017     Published: April 25, 2017 ABSTRACT The long noncoding RNA HOTAIR promotes the development and progression of several tumors. Here, the clinical significance and role of HOTAIR in renal cell carcinoma (RCC) tumorigenesis were explored. The results showed that increased expression of HOTAIR predicted a poor prognosis of RCC after surgery. HOTAIR promoted RCC cell proliferation and growth in vitro and in vivo . The expressions of HOTAIR and Salvador homolog 1 (SAV1) were inversely correlated in clinical RCC samples. HOTAIR downregulated SAV1 by directly binding to the SAV1 protein and enhanced histone H3K27 methylation. Loss of function of SAV1 activated the Hippo pathway. HOTAIR could be a potential therapeutic target in RCC.

The long noncoding RNA HOTAIR activates the Hippo pathway by directly binding to SAV1 in renal cell carcinoma

Matrix metalloproteinase-2 (MMP-2) is a member of the MMP family, which is associated with numerous types of cancer. Although it has been widely reported, the prognostic value of MMP-2 expression in prostate cancer (PCa) remains controversial. Thus, the present meta-analysis was conducted to investigate the association and prognostic value of MMP-2 expression in PCa. PubMed, Cochrane Library and the China National Knowledge Infrastructure databases were searched for all the published case-control studies on the association between MMP-2 expression and PCa until July 2015. The odd ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the association of MMP-2 expression and PCa. ORs and 95% CIs were applied to clarify this association. Several subgroup analyses were also conducted according to different indexes in the case group. In total, 8 studies including 675 patients were included in the final meta-analysis. The results of the meta-analysis showed that MMP-2 expression in the PCa group was significantly higher than that in the benign prostatic hyperplasia (BPH) group (95% CI, 0.06-0.15; Z=10.48; P<0.00001). Furthermore, MMP-2 expression was significantly associated with Gleason Score (95% CI, 0.18-0.68; Z=3.09; P=0.002) and clinical stages (95% CI, 0.12-0.82; Z=2.36; P=0.02), and not significantly associated with Gleason score serum prostate specific antigen (95% CI, 0.30-1.66; Z=0.80; P=0.43). In conclusion, MMP-2 is overexpressed in PCa tissues compared with BPH. The expression of MMP-2 was significantly associated with the grade of PCa malignancy.

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Association between MMP-2 expression and prostate cancer: A meta-analysis

The leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is highly expressed in many human malignancies and is correlated with poor prognosis. However, the function of LETM1 in bladder cancer still remains unknown. In the present study, we analyzed the expression levels of LETM1 in bladder cancer tissues and non-cancerous tissues as well as in four bladder cancer cell lines (T24, EJ, 5637 and J82) and a human bladder epithelial immortalized cell line SV-HUC-1. Small interfering RNA (siRNA) was employed to knockdown the expression of LETM1 in the T24 cells. The proliferation of T24 cells was significantly repressed as evaluated by CCK-8 assays. Transwell migration and invasion assays indicated that knockdown of LETM1 suppressed cell migration and invasion significantly. Flow cytometric analysis revealed that cells had accumulated at the S-phase when the expression of LETM1 was suppressed. Moreover, we found that several oncogenic proteins in the Wnt/β-catenin signaling pathway, namely β-catenin, cyclin D1 and c-Myc were significantly decreased by the LETM1 siRNA. Collectively, these results revealed that the knockdown of LETM1 exhibited tumor suppressive effects, possibly by controlling the downstream Wnt/β-catenin signaling pathway.

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Suppression of LETM1 by siRNA inhibits cell proliferation and invasion of bladder cancer cells

Accumulating evidence suggested that microRNA (miRNA) plays important regulatory roles in the initiation and development of various cancers. Previous study showed that microRNA-206 (miR-206) is dysregulated in human bladder cancer tissues, however, the biological function and underlying mechanisms of miR-206 in human bladder cancer remain unknown. In the present study, we aimed to investigate the clinical significance of miR-206 and its target gene YRDC in human bladder cancer, and to determine its effects on oncogenic phenotypes of this disease. Our results showed that miR-206 expression was downregulated significantly in bladder cancer tissues and cell lines compared with adjacent normal bladder tissues and human bladder epithelial immortalized SV-HUC-1 cell line, respectively. Overexpression of miR-206 reduced the expression of YRDC and inhibited bladder cancer cell proliferation, colony formation, migration, invasion and induced cell cycle arrest at G0/G1 phase. In addition, knockdown of YRDC exhibited similar effects with miR-206 overexpression in bladder cancer cells and restoration of YRDC partially reversed the effects of miR-206 in bladder cancer cells. These findings indicated that mir-206 might be a novel target for bladder cancer therapy by targeting YRDC.

MicroRNA-206 acts as a tumor suppressor in bladder cancer via targeting YRDC

The leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) has been reported to serve an important role in a number of human malignancies and is correlated with poor prognosis However, little is known about the role of LETM1 in renal cell carcinoma (RCC) In the present study, the expression levels of LETM1 were investigated in RCC cell lines (Caki-1, 786-O, OS-RC-2, A498 and ACHN) and the HK-2 normal human renal tubular epithelial cell line Short interfering RNA (siRNA) was used to knock down the expression of LETM1 in 786-O and A498 cells The results indicated that the constitutive expression of LETM1 was notably upregulated in RCC cell lines Knockdown of LETM1 significantly decreased cell proliferation, migration and invasion Mechanistically, it was revealed that the knockdown of LETM1 expression sharply downregulated the protein expression of β-Catenin, Cyclin D1 and c-Myc in 786-O and A498 cells In conclusion, these results suggest that knockdown of LETM1 exhibits tumor suppressive effects, at least in part by controlling the downstream Wnt/β-Catenin signaling pathway Therefore, LETM1 may act as a novel therapeutic target for the treatment of RCC

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Tiancheng Xie

Papers

The long noncoding RNA HOTAIR activates the Hippo pathway by directly binding to SAV1 in renal cell carcinoma

Association between MMP-2 expression and prostate cancer: A meta-analysis

Suppression of LETM1 by siRNA inhibits cell proliferation and invasion of bladder cancer cells

MicroRNA-206 acts as a tumor suppressor in bladder cancer via targeting YRDC

Knockdown of LETM1 inhibits proliferation and metastasis of human renal cell carcinoma cells.