Jianxun Wang

Biogenesis of circular RNAs and their roles in cardiovascular development and pathology

Circular RNAs (circRNAs) are a newly discovered type of RNA generated by back‐splicing of precursor mRNA and found in many species. They are, expressed in a tissue‐specific manner and fulfill regulatory activities in many biological processes. Recent research has revealed that circRNAs play critical roles in the development and pathologies of the cardiovascular system. Some of these circRNAs show aberrant expression and regulatory activities during heart disease including heart failure and cardiac infarction and hypertrophy. These findings suggest that circRNAs might be a suitable target for the treatment and prevention of heart disease. In this review, we summarize the latest research on the biogenesis and functions of circRNAs with emphasis on the regulatory roles of circRNAs in the development and pathologies of the cardiovascular system.

Traction with dental floss and endoscopic clip improves trainee success in performing gastric endoscopic submucosal dissection (ESD): a live porcine study (with video)

AbstractBackground and aimsnEndoscopic submucosal dissection (ESD) is a prolonged procedure with serious adverse events. The clip with line traction method was reported to improve ESD. However, there was no comparison with conventional ESD especially for trainees. We report here on the feasibility and efficacy of traction using dental floss with endoscopic clip to facilitate ESD versus conventional method for ESD trainees.MethodsTwenty simulated gastric lesions, paired with location and size, were created in porcine stomachs using a standard template. After a circular incision was made, submucosal dissection (control, nxa0=xa010) was performed with standard ESD, while the study (clip, nxa0=xa010) was performed with traction using dental floss and endoclip. Primary outcome was speed of submucosal dissection. Secondary outcome included frequency of submucosal injection and adverse event.ResultsCompared with controls, median procedure time was significantly shorter in the clip group (5.6xa0±xa01.1 vs. 13.6xa0±xa02.5xa0min, Pxa0=xa00.003), with a significantly faster submucosal dissection time (1.8xa0±xa00.3 vs. 0.6xa0±xa00.1xa0cm2/min, Pxa0=xa00.001) and less frequent submucosal injection (5.7xa0±xa00.6 vs. 8.5xa0±xa01.0 times, Pxa0=xa00.024). There were no perforations in either group, but less adverse events (bleeding and injury to muscularis propria) in the clip group (1 vs. 7, Pxa0=xa00.068, αxa0=xa00.1).ConclusionsTraction provided by dental floss and endoclip improves visualization of the submucosal layer during ESD. It allows a faster and safer gastric ESD especially among trainees in the early learning phase.

Phosphorylation of apoptosis repressor with caspase recruitment domain by protein kinase CK2 contributes to chemotherapy resistance by inhibiting doxorubicin induced apoptosis

The development of cancer resistance to chemotherapy is the major obstacle to cancer therapy. Here, we identified that the phosphorylation of apoptosis repressor with caspase recruitment domain (ARC) at threonine 149 was essential to inhibit doxorubicin (DOX) induced apoptosis and mitochondrial fission in cancer cells. Our further study showed that casein kinase II (CK2) inhibitors could decrease the phosphorylation levels of ARC and make cancer cells sensitive to undergoing apoptosis. Furthermore, CK2α and CK2α, catalytic subunits of CK2, were observed to translocate into nuclear in cancer cells with the treatment of DOX. Finally, the synergistically therapeutic effect by combining DOX and CK2 inhibitor was confirmed in tumor xenograft model. Taken together, our results revealed that CK2-mediated phosphorylation of ARC contributed to chemotherapy resistance by inhibiting DOX induced apoptosis and combining DOX with CK2 inhibitor could induce apoptosis of cancer cells synergistically by down-regulating the phosphorylation of ARC. Therefore, development of new therapeutic strategies based on ARC and CK2, is promising for overcoming cancer resistance to chemotherapy.

Long noncoding RNA gastric cancer-related lncRNA1 mediates gastric malignancy through miRNA-885-3p and cyclin-dependent kinase 4

Gastric cancer (GC) is one of the most common malignancy and the third leading cancer-related death in China. Long noncoding RNAs (lncRNAs) have been implicated in numerous tumors, including GC, however, the mechanism of many functional lncRNAs is still unclear. In this study, we identified the abundantly expressed lncRNA, RP11-290F20.3, in GC cells and patient tumor tissues. We named this lncRNA as GC-related lncRNA1 (GCRL1), which could regulate gastric cell proliferation and metastasis, both in vitro and in vivo. Mechanistically, miRNA-885-3p (miR-885-3p) could inhibit the cell proliferation and metastasis in GC by negatively regulating the expression of cyclin-dependent kinase 4 (CDK4) at the post-transcriptional level. Further, GCRL1 promoted the cell proliferation and metastasis by sponging miR-885-3p and hence, positively regulating CDK4 in GC cells. Taken together, our results demonstrate a novel regulatory axis of malignant cell proliferation and invasion in GC, comprising GCRL1, miR-885-3p, and CDK4, which may serve as a potential therapeutic target in GC.

Epigenetic regulation of long non-coding RNAs in gastric cancer

Gastric cancer is one of the most common cancers and is the second leading cause of cancer mortality worldwide. Therefore, it is urgent to explore new molecular biomarkers for early diagnosis, early treatment and prognosis for gastric cancer patients. Recently, increasing evidence has shown that epigenetic changes, such as aberrant DNA methylation, histone modifications, and noncoding RNAs (ncRNAs) expression, play substantial roles in the development and progression of malignancies. Among these changes, long non-coding RNAs (lncRNAs), a novel class of ncRNAs, are emerging as highly versatile actors in a variety of cellular processes by regulating gene expression at the epigenetic level as well as at the transcriptional and post-transcriptional levels. Hundreds of lncRNAs become dysregulated in the various pathological processes of gastric cancer, and multiple lncRNAs have been reported to function as tumor-suppressors or oncogenes, although the underlying mechanisms are still under investigation. Here, we provide an overview of the epigenetic regulation of chromatin and the molecular functions of lncRNAs; we focus on lncRNA-mediated epigenetic regulation of cancer-related gene expression in gastric cancer, as well as discuss the clinical implications of lncRNAs on epigenetic-related cancer treatments, which may contribute helpful approaches for the development of new potential strategies for future diagnosis and therapeutic intervention in human cancers.

MicroRNA-195: a review of its role in cancers

MicroRNAs (miRNAs) are small and highly conserved noncoding RNAs that regulate gene expression at the posttranscriptional level by binding to the 3′-UTR of target mRNAs. Recently, increasing evidence has highlighted their profound roles in various pathological processes, including human cancers. Deregulated miRNAs function as either oncogenes or tumor suppressor genes in multiple cancer types. Among them, miR-195 has been reported to significantly impact oncogenicity in various neoplasms by binding to critical genes and signaling pathways, enhancing or inhibiting the progression of cancers. In this review, we focus on the expression of miR-195 in regulatory mechanisms and tumor biological processes and discuss the future potential therapeutic implications of diverse types of human malignancies.

The Long Noncoding RNA D63785 Regulates Chemotherapy Sensitivity in Human Gastric Cancer by Targeting miR-422a

Gastric cancer is one of the most prevalent tumor types in the world. Chemotherapy is the most common choice for cancer treatment. However, chemotherapy resistance and adverse side effects limit its clinical applications. Aberrant expression of long noncoding RNAs (lncRNAs) has been found in various stages of gastric cancer development and progression. In this study, we identified that an oncogenic lncRNA, long intergenic non-protein-coding RNA D63785 (lncR-D63785), is highly expressed in gastric cancer tissues and cells. Silencing of lncR-D63785 inhibited cell proliferation, cell migration and invasion in gastric cancer cell lines and reduced tumor volume and size in mice. We found that the expression of lncR-D63785 was inversely correlated with microRNA 422a (miR-422a) expression, which was involved in the downregulation of expression of myocyte enhancer factor-2D (MEF2D) and drug sensitivity. Knockdown of lncR-D63785 increased the expression of miR-422a and the sensitivity of gastric cancer cells to apoptosis induced by the anticancer drug doxorubicin (DOX). This indicates that lncR-D63785 acts as a competitive endogenous RNA (ceRNA) of miR-422a and promotes chemoresistance by blocking miR-422-dependent suppression of MEF2D. Together, our results suggest that the therapeutic suppression of lncR-D63785 alone or in combination with chemotherapeutic agents may be a promising strategy for treating gastric cancer.

Molecular mechanism and therapy application of necrosis during myocardial injury

Necrosis is an ancient topic which gains new attraction in the research area these years. There is no doubt that some necrosis can be regulated by genetic manipulation other than an accidental cell death resulting from physical or chemical stimuli. Recent advances in the molecular mechanism underlying the programmed necrosis show a fine regulation network which indicates new therapy targets in human diseases. Heart diseases seriously endanger our health and have high fatality rates in the patients. Cell death of cardiac myocytes is believed to be critical in the pathogenesis of heart diseases. Although necrosis is likely to play a more important role in cardiac cell death than apoptosis, apoptosis has been paid much attention in the past 30 years because it used to be considered as the only form of programmed cell death. However, recent findings of programmed necrosis and the related signalling pathways have broadened our horizon in the field of programmed cell death and promote new pharmacological application in the treatment of heart diseases. In this review, we summarize the advanced progress in these signalling pathways and discuss the pathos‐physiological relevance and therapeutic implication of targeting necrosis in heart diseases treatment.

MicroRNA regulation of Toll-like receptor signaling pathways in teleost fish

ABSTRACT The innate immune system is the first line defense mechanism that recognizes, responds to, controls or eliminates invading pathogens. Toll‐like receptors (TLRs) are a critical family of pattern recognition receptors (PRRs) tightly regulated by complex mechanisms involving many molecules to ensure a beneficial outcome in response to foreign invaders. MicroRNAs (miRNAs), a transcriptional and posttranscriptional regulator family in a wide range of biological processes, have been identified as new molecules related to the regulation of TLR‐signaling pathways in immune responses. To date, at least 22 TLR types have been identified in more than a dozen different fish species. However, the functions and underlying mechanisms of miRNAs in the regulation of inflammatory responses related to the TLR‐signaling pathway in fish is lacking. In this review, we summarize the regulation of miRNA expression profiles in the presence of TLR ligands or pathogen infections in teleost fish. We focus on the effects of miRNAs in regulating TLR‐signaling pathways by targeting multiple molecules, including TLRs themselves, TLR‐associated signaling proteins, and TLR‐induced cytokines. An understanding of the relationship between the TLR‐signaling pathways and miRNAs may provide new insights for drug intervention to manipulate immune responses in fish. Graphical abstract Figure. No Caption available. HighlightsmiRNAs expressions are regulated by TLR‐signaling pathways.TLR‐responsive miRNAs are regulated in a MyD88/NF‐&kgr;B signaling dependent manner.TLRs, TLR‐associated signaling proteins and cytokines are targets of miRNAs.There is a bidirectional regulation between miRNAs and TLR‐signaling pathways.

Function and regulation of mitofusin 2 in cardiovascular physiology and pathology

Mitochondrial dynamics with constant fusion and fission plays vital roles in regulating cellular biological processes. Mitofusin 2 (Mfn2) is dynamin-related protein whose activity promotes mitochondrial fusion and maintains the homeostasis of mitochondrial dynamics. Advanced studies have demonstrated that Mfn2 is a multifunctional protein with signaling roles beyond fusion. Mfn2 is actively involved in various biological processes under both physical and pathological conditions, including mitochondrial transport and the interaction between endoplasmic reticulum/sarcoplasmic reticulum and mitochondria, as well as cell metabolism, apoptosis and autophagy. This review summarises the structural and functional properties of Mfn2, with focus on recent advances in its regulatory role in cardiovascular system.