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[en] Highlights: • HBx upregulates the expression of SIRT2 in HCC cell lines. • SIRT2 promotes the transcription and replication of HBV. • SIRT2 facilitates HBx-mediated hepatocarcinogenesis. Sirtuin 2 (SIRT2) is a class III histone deacetylase that has been implicated to promote HCC development. However, the functional role of SIRT2 in HBV is still unclear. In this study, we found that HBV could upregulate SIRT2 expression. Additionally, HBx could activate SIRT2 promoter to upregulate the mRNA and protein level of SIRT2. Furthermore, we found that SIRT2 could facilitate HBV transcription and replication. Finally, we demonstrated that upregulation of SIRT2 by HBx promoted hepatocarcinogenesis. In summary, our findings revealed a novel function of SIRT2 in HBV and HBV-mediated HCC. First, SIRT2 could promote HBV replication. And then HBx-elevated SIRT2 could enhance the transformation of HBV-mediated HCC. Those findings highlight the potential role of SIRT2 in HBV and HBV-mediated HCC by interaction with HBx.
[en] Cardiac hypertrophy is determined by an increase of cell size in cardiomyocytes (CMCs). Among the cellular processes regulating the growth of cell size, the increase of protein synthesis rate represents a critical event. Most of translational factors promoting protein synthesis stimulate cardiac hypertrophy. In contrast, activity of translational repressor factors, in cardiac hypertrophy, is not fully determined yet. Here we report the effect of a translational modulator, eIF6/p27BBP in the hypertrophy of neonatal rat CMCs. The increase of eIF6 levels surprisingly prevent the growth of cell size induced by phenylephrine, through a block of protein synthesis without affecting skeletal rearrangement and ANF mRNA expression. Thus, this work uncovers a new translational cardiac regulator independent by other well-known factors such as mTOR signalling or eIF2β.
[en] Exosomes contain cargoes of proteins, lipids, micro-ribonucleic acids, and functional messenger RNAs, and they play a key role in cell-to-cell communication and hold valuable information about biological processes such as disease pathology. To harvest their potentials in disease diagnostics, prognostics, and therapeutics, exosome isolation is a crucial first step in providing pure and intact samples for both research and clinical purposes. Unfortunately, conventional methods for exosome separation suffer from low purity, low capture efficiency, long processing time, large sample volume requirement, the need for dedicated equipment and trained personnel, and high cost. In the last decade, microfluidic devices, especially those that incorporate nanostructures, have emerged as superior alternatives for exosome isolation and detection. In this review, we examine microfluidic platforms, dividing them into six categories based on their capture mechanisms: passive-structure-based affinity, immunomagnetic-based affinity, filtration, acoustofluidics, electrokinetics, and optofluidics. Here, we start out exploring the research and clinical needs that translate into important performance parameters for new exosome isolation designs. Then, we briefly introduce the conventional methods and discuss how their failure to meet those performance standards sparks an intense interest in microfluidic device innovations. The essence of this review is to lead an in-depth discussion on not only the technicality of those microfluidic platforms, but also their strengths and weaknesses with regards to the performance parameters set forth. To close the conversation, we call for the inclusion of exosome confirmation and contamination evaluation as part of future device development and performance assessment process, so that collectively, efforts towards microfluidics and nanotechnology for exosome isolation and analysis may soon see the light of real-world applications. (topical review)
[en] Highlights: • High expression of ADAM17 is associated with oxaliplatin chemosensitivity. • Chronic oxaliplatin exposure established drug-resistant cell line HCT-8/L-OHP. • Down regulation of ADAM17 can enhance sensitivity and reverse resistance to oxaliplatin. • Downregulation of ADAM17 inhibit cell proliferation, induce apoptosis via EGFR/PI3K/AKT signaling pathway. We investigated the role of a disintegrin and metalloproteinase 17 (ADAM17) in chemo resistance, and to clarify the mechanism underlying reverse of L-OHP resistance by knockdown of ADAM17. CRC tissues with corresponding adjacent normal tissues were collected. The mRNA and protein expression of ADAM17 in tissues were detected by RT-qPCR, immunohistochemistry and Western blot. The prognostic impact of ADAM17 expression were then validated in TCGA database to confirm the results. Resistance to oxaliplatin was induced in HCT-8 (HCT-8/L-OHP) colorectal cancer cell line by exposing cell to increasing concentrations of L-OHP. MTT were used to evaluate the resistance to L-OHP. Subsequently, Knockdown of ADAM17 in HCT-8 and HCT-8/L-OHP cells to explore the mechanism through which ADAM17 shRNA reverses L-OHP resistance. Our result showed that ADAM17 was higher expression in the cancerous tissue and related to the chemosensitivity. Moreover, ADAM17 shRNA, AG1478 and LY294002 could inhibit cell proliferation, induce apoptosis and increase oxaliplatin sensitivity in HCT-8/L-OHP and parental colorectal cancer cell line, but nonsense shRNA did not show this effect. Western blot analysis further confirmed that EGFR/PI3K/AKT signaling pathway is involved in ADAM17 shRNA inhibiting proliferation and chemosensitivity of HCT-8/L-OHP and HCT-8 cells. The present study provides the evidence that downregulation of ADAM17 could increase the sensitivity to chemotherapy, inhibit cell proliferation, induce apoptosis, and reverse oxaliplatin resistance via suppression of the EGFR/PI3K/AKT signaling pathway in CRC.
[en] Highlights: • Different expressed miRNAs and mRNAs were profiled in lowly and highly metastatic SACC cell lines. • Multiple regulatory interactions between miRNAs and mRNAs may contribute to SACC metastasis. • miR-338–5p/3p and their target LAMC2 function on metastasis of multiple types of cancer. Salivary adenoid cystic carcinoma (SACC) is often accompanied with poor prognosis due to local recurrence, distant metastasis, and perineural invasion. The mechanism involved in SACC metastasis is not yet fully understood. In this study, we profiled the expression of messenger RNA (mRNA) and microRNA (miRNA) in a SACC cell line, ACC-2, and a highly metastatic SACC cell line, ACC-M, using high-throughput sequencing. We discovered that: (1) differentially expressed (DE) mRNAs and DE miRNAs are potentially involved in SACC metastasis; (2) multiple regulatory interactions between DE miRNAs and DE mRNAs exist; and (3) miR-338–5p/3p target LAMC2 to impair motility and invasion of ACC-M and MDA-MB-231 cells. In conclusion, our study integrated the regulatory effects of miRNAs and mRNAs on SACC metastasis and provided a potential application for miRNAs in future therapeutic intervention.
[en] Highlights: • MiR-148a-3p is downregulated in tendinopathy and positively correlated with CD34. • KLF6 is identified as a novel target of miR-148a-3p. • MiR-148a-3p/KLF6 regulates Tsp-4 expression of Tenocyte mediating angiogenesis during tendinopathy development. • The first study investigates the role of miR-148a-3p in angiogenesis of tendinopathy. Tendinopathy is a common musculoskeletal disorder with characteristic hypervascularity. The mechanism of angiogenesis in tendinopathy remains unclear. The present study aimed to investigate the roles of miR-148a-3p in angiogenesis development of tendinopathy. In this study, we demonstrated that miR-148a-3p expression was increased in tendinopathy tissues and positively correlated with CD34 levels which is a specific marker for angiogenesis. We identified Krüppel-like factor 6 (KLF6) as a direct target gene of miR-148a-3p in tenocytes. Furthermore, reduced levels of KLF6 in tendinopathy tissues was showed using qRT-PCR and immunohistochemical analysis, compared with controls. A negative correlation between the levels of KLF6 mRNA and miR-148a-3p was observed. Then, we verified that miR-148a-3p could regulate Tsp-4 expression by targeting KLF6 in tenocyte and was positively correlated with Tsp-4 levels in tendinopathy tissues. In a coculture system of tenocytes with endothelial cells (ECs), we observed that transfection of Lv-miR-148a-3p markedly upregulated EC angiogenesis. In summary, our data establish a novel molecular mechanism by which miR-148a-3p upregulates Tsp-4 expression in tenocytes to promote EC angiogenesis by targeting KLF6, which could be helpful for the treatment of tendinopathy in the future.
[en] Highlights: • LncRNAs as a ceRNA can regulate the expression of target genes, which can influence on tumorigenesis and tumor progression. • We firstly developed novel lncRNAs as well as their action mechanisms in CCA. • We identified a total of 1411 differentially expressed lncRNAs, 3494 mRNAs, and 64 miRNAs. • A ceRNA network consisting of 116 lncRNAs, 14 miRNAs and 59 mRNAs was established. Long non-coding RNAs (lncRNAs) can interact with microRNAs (miRNAs) as a competing endogenous RNA (ceRNA) to regulate the expression of target genes, which can largely influence on tumorigenesis and tumor progression. However, the role of lncRNA-mediated ceRNAs in cholangiocarcinoma (CCA) remains unknown. This study aimed to develop novel lncRNAs as well as their action mechanisms in CCA.
[en] Heat shock protein 90 family members (HSP90s), as molecular chaperones, have conserved roles in the physiological processes of eukaryotes regulating cytoprotection, increasing host resistance and so on. However, whether HSP90s affect regeneration in animals is unclear. Planarians are emerging models for studying regeneration in vivo. Here, the roles of three hsp90 genes from planarian Dugesia japonica are investigated by WISH and RNAi. The results show that: (1) Djhsp90s expressions are induced by heat and cold shock, tissue damage and ionic liquid; (2) Djhsp90s mRNA are mainly distributed each side of the body in intact worms as well as blastemas in regenerative worms; (3) the worms show head regression, lysis, the body curling and the regeneration arrest or even failure after Djhsp90s RNAi; (4) Djhsp90s are involved in autophagy and locomotion of the body. The research results suggest that Djhsp90s are not only conserved in cytoprotection, but also involved in homeostasis maintenance and regeneration process by regulating different pathways in planarians.
[en] The T-cell immunoglobulin and mucin domain (TIM) family is associated with autoimmune diseases, but its expression level in the immune cells of systemic lupus erythematosus (SLE) patients is not known. The aim of this study was to investigate whether the expression of TIM-3 mRNA is associated with pathogenesis of SLE. Quantitative real-time reverse transcription-polymerase chain reaction analysis (qRT-PCR) was used to determine TIM-1, TIM-3, and TIM-4 mRNA expression in peripheral blood mononuclear cells (PBMCs) from 132 patients with SLE and 62 healthy controls. The PBMC surface protein expression of TIMs in PBMCs from 20 SLE patients and 15 healthy controls was assayed by flow cytometry. Only TIM-3 mRNA expression decreased significantly in SLE patients compared with healthy controls (P<0.001). No significant differences in TIM family protein expression were observed in leukocytes from SLE patients and healthy controls (P>0.05). SLE patients with lupus nephritis (LN) had a significantly lower expression of TIM-3 mRNA than those without LN (P=0.001). There was no significant difference in the expression of TIM-3 mRNA within different classes of LN (P>0.05). Correlation of TIM-3 mRNA expression with serum IgA was highly significant (r=0.425, P=0.004), but was weakly correlated with total serum protein (r_s=0.283, P=0.049) and serum albumin (r_s=0.297, P=0.047). TIM-3 mRNA expression was weakly correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; r_s=-0.272, P=0.032). Our results suggest that below-normal expression of TIM-3 mRNA in PBMC may be involved in the pathogenesis of SLE
[en] Highlights: • Revealed the expression characterization of circRNAs in dog atrial tissue. • Compared differentially expressed circRNAs between atrial fibrillation and control dog. • Found extensive interaction among circRNAs and AF related miRNAs and mRNAs. Circular RNAs (circRNAs) have emerged as novel molecules of interest in gene regulation as other noncoding RNAs, and participating in the process of many diseases. However, the expression and functions of circRNAs in Rapid atrial pacing (RAP) dog atrial tissue still unknown. 12 canines were randomly assigned to control and pacing group. RAP at 500 beats per minute was maintained 14 days in the pacing group. The expression characterization of circRNAs were revealed by high-throughput sequencing. We totally predicted 15,990 circRNAs in dog atrial tissues. Moreover, we found 146 differentially expressed circRNAs between control and RAP dogs. Five circRNAs were selected for subsequent RT-PCR validation, and four circRNAs confirmed with the high throughput sequencing analysis. GO analysis showed that the differentially expressed circRNAs might involve in the process of “structural constituent of cytoskeleton, ion channel activity”. We explored the circRNA-miRNA interaction network, and found extensive interaction among differentially expressed circRNAs and AF related miRNAs and mRNAs. Our work firstly identified the characterization of circRNAs in the dog atrial, and revealed the differentially expressed circRNAs in the RAP dog, this might lay a solid foundation on the function of circRNA in the mechanisms of AF.