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

Chemoresistance has long been recognized as a major obstacle in cancer therapy. Clarifying the underlying mechanism of chemoresistance would result in novel strategies to improve patient’s response to chemotherapeutics. lncRNA expression levels in gastric cancer (GC) cells was detected by quantitative real-time PCR (qPCR). MALAT1 shRNAs and overexpression vector were transfected into GC cells to down-regulate or up-regulate MALAT1 expression. In vitro and in vivo assays were performed to investigate the functional role of MALAT1 in autophagy associated chemoresistance. We showed that chemoresistant GC cells had higher levels of MALAT1 and increased autophagy compared with parental cells. Silencing of MALAT1 inhibited chemo-induced autophagy, whereas MALAT1 promoted autophagy in gastric cancer cells. Knockdown of MALAT1 sensitized GC cells to chemotherapeutics. MALAT1 acts as a competing endogenous RNA for miR-23b-3p and attenuates the inhibitory effect of miR-23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells. Taken together, our study revealed a novel mechanism of lncRNA-regulated autophagy-related chemoresistance in GC, casting new lights on the understanding of chemoresistance.

/pdf/long-noncoding-rna-malat1-regulates-autophagy-associated-1rdrrdtwv2.pdf

Long noncoding RNA MALAT1 regulates autophagy associated chemoresistance via miR-23b-3p sequestration in gastric cancer.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the second most lethal human cancer. A portion of patients with advanced HCC can significantly benefit from treatments with sorafenib, adriamycin, 5-fluorouracil and platinum drugs. However, most HCC patients eventually develop drug resistance, resulting in a poor prognosis. The mechanisms involved in HCC drug resistance are complex and inconclusive. Human transcripts without protein-coding potential are known as noncoding RNAs (ncRNAs), including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), long noncoding RNAs (lncRNAs) and circular RNA (circRNA). Accumulated evidences demonstrate that several deregulated miRNAs and lncRNAs are important regulators in the development of HCC drug resistance which elucidates their potential clinical implications. In this review, we summarized the detailed mechanisms by which miRNAs and lncRNAs affect HCC drug resistance. Multiple tumor-specific miRNAs and lncRNAs may serve as novel therapeutic targets and prognostic biomarkers for HCC.

/pdf/the-emerging-role-of-micrornas-and-long-noncoding-rnas-in-24pvjz8ga4.pdf

The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) can play a pivotal role in regulation of diverse cellular processes. In particular, lncRNAs can serve as master gene regulators at transcriptional and posttranscriptional levels, leading to tumorigenesis. In this review, we discuss latest developments in lncRNA-meditated gene expression at the post-transcriptional level, including gene splicing, mRNA stability, protein stability and nuclear trafficking.

Emerging roles of lncRNAs in the post-transcriptional regulation in cancer.

Epithelial mesenchymal transition (EMT), the adoption by epithelial cells of a mesenchymal-like phenotype, is a process co-opted by carcinoma cells in order to initiate invasion and metastasis. In addition, it is becoming clear that is instrumental to both the development of drug resistance by tumour cells and in the generation and maintenance of cancer stem cells. EMT is thus a pivotal process during tumour progression and poses a major barrier to the successful treatment of cancer. Non-coding RNAs (ncRNA) often utilize epigenetic programs to regulate both gene expression and chromatin structure. One type of ncRNA, called long non-coding RNAs (lncRNAs), has become increasingly recognized as being both highly dysregulated in cancer and to play a variety of different roles in tumourigenesis. Indeed, over the last few years, lncRNAs have rapidly emerged as key regulators of EMT in cancer. In this review, we discuss the lncRNAs that have been associated with the EMT process in cancer and the variety of molecular mechanisms and signalling pathways through which they regulate EMT, and finally discuss how these EMT-regulating lncRNAs impact on both anti-cancer drug resistance and the cancer stem cell phenotype.

https://www.mdpi.com/2072-6694/9/4/38/pdf

Long Non-Coding RNAs: Key Regulators of Epithelial-Mesenchymal Transition, Tumour Drug Resistance and Cancer Stem Cells

Considerable evidences have shown that autophagy has an important role in tumor chemoresistance. However, it is still unknown whether the lncRNA HULC (highly upregulated in liver cancer) is involved in autophagy and chemoresistance of hepatocellular carcinoma (HCC). In this study, we for the first time demonstrated that treatment with antitumor reagents such as oxaliplatin, 5-fluorouracil and pirarubicin (THP) dramatically induced HULC expression and protective autophagy. Silencing of HULC sensitized HCC cells to the three antitumor reagents via inhibiting protective autophagy. Ectopic expression of HULC elicited the autophagy of HCC cells through stabilizing silent information regulator 1 (Sirt1) protein. The investigation for the corresponding mechanism by which HULC stabilized Sirt1 revealed that HULC upregulated ubiquitin-specific peptidase 22 (USP22), leading to the decrease of ubiquitin-mediated degradation of Sirt1 protein by removing the conjugated polyubiquitin chains from Sirt1. Moreover, we found that miR-6825-5p, miR-6845-5p and miR-6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. In addition, we showed that the level of HULC was positively correlated with that of Sirt1 protein in human HCC tissues. Collectively, our data reveals that the pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents, suggesting that this pathway may be a novel target for developing sensitizing strategy to HCC chemotherapy.

LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells

Local amorphous phases often appear in NiTi shape memory alloys (SMAs) which undergo a large degree of cold plastic deformation. Fracture damage is a common failure mode of NiTi SMAs in engineering application and it is usually caused by the crack initiation and propagation. The crack initiation and propagation behaviours in NiTi SMA parts containing amorphous phases have not been reported so far. In the present study, extended finite elements method (XFEM) was applied to investigate the influence of amorphous phase on crack initiation and propagation behaviours in a notched NiTi SMA specimen processed by cold plastic deformation. The results show that the amorphous zone has a significant influence on both the crack initiation and the crack propagation. Crack is easier induced if there exists amorphous phase in the NiTi SMA but it is difficult for the crack to pass through the amorphous zone.

Influence of amorphous phase on crack initiation and propagation behaviours in NiTi shape memory alloy based on extended finite element simulation

OBJECTIVE
To investigate the protective effect of cannabinoid receptor 2 (CB2) activation against acute lung injury in rats with lipopolysaccharide (LPS)-induced sepsis and explore the underlying mechanism.


METHODS
Forty-eight SD rats were randomly assigned into control group, model group, CB2 agonist group and P38 MAPK inhibitor group (n=12). In the latter 3 groups, the rats received intraperitoneal injection of LPS to induce sepsis, and the control rats were given saline injection. In CB2 agonist group, JWH133 (3 mg/kg) was injected intraperitoneally 30 min before LPS injection; in P38 MAPK inhibitor group, the rats received intraperitoneal injection of SB203580 (5 mg/kg) 30 min prior to JWH133 injection. The changes in lung histopathology, water content, fluid clearance rate, inflammatory factors, pulmonary expressions of CB2 and tight junctionrelated genes, and phosphorylation of P38 MAPK in the lung tissues were examined.


RESULTS
The rat models of sepsis showed severe damage of alveolar structures with significantly decreased fluid clearance rate, lowered pulmonary expressions of CB2, occludin and ZO-1 mRNA and proteins, increased water content in the lung tissue, and increased phosphorylation level of P38 MAPK and TNF-α and IL-1β levels in lung lavage fluid (all P < 0.05). Treatment with JWH133 improved alveolar pathology in the septic rats, but there was still inflammatory infiltration; lung tissue water content, phosphorylation of P38 MAPK, and TNF-α and IL-1β levels in lung lavage fluid were all significantly decreased, and the fluid clearance rate, pulmonary expressions of CB2, occludin and ZO-1 were significantly increased (all P < 0.05). Additional treatment with SB203580 resulted in further improvements of alveolar pathologies, lowered phosphorylation levels of P38 MAPK in the lung tissue and TNF-α and IL-1β levels in lung lavage fluid, and increased the protein expressions of occludin and ZO-1 (P < 0.05) without causing significant changes in mRNA and protein expression of CB2 (P > 0.05).


CONCLUSION
In rats with LPS-induced sepsis, activation of CB2 can inhibit the p38 MAPK signaling pathway, reduce the release of inflammatory factors in the lung tissues, promote tight junction protein expressions, and thus offer protection against acute lung injury.

S Jiang

Papers

LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells

Influence of amorphous phase on crack initiation and propagation behaviours in NiTi shape memory alloy based on extended finite element simulation

[Activation of cannabinoid receptor 2 alleviates acute lung injury in rats with lipopolysaccharide-induced sepsis].