AS (alternative splicing) is a fundamental process by which a gene can generate multiple distinct mRNA transcripts to increase protein diversity. Defects in AS influence the occurrence and development of many diseases, including cancers, and are frequently found to participate in various aspects of cancer biology, such as promoting invasion, metastasis, apoptosis resistance and drug resistance. NcRNAs (noncoding RNAs) are an abundant class of RNAs that do not encode proteins. NcRNAs include miRNAs (microRNAs), lncRNAs (long noncoding RNAs), circRNAs (circular RNAs) and snRNAs (small nuclear RNAs) and have been proven to act as regulatory molecules that mediate cancer processes through AS. NcRNAs can directly or indirectly influence a plethora of molecular targets to regulate cis-acting elements, trans-acting factors, or pre-mRNA transcription at multiple levels, affecting the AS process and generating alternatively spliced isoforms. Consequently, ncRNA-mediated AS outcomes affect multiple cellular signaling pathways that promote or suppress cancer progression. In this review, we summarize the current mechanisms by which ncRNAs regulate AS in cancers and discuss their potential clinical applications as biomarkers and therapeutic targets.

/pdf/noncoding-rnas-regulate-alternative-splicing-in-cancer-3kazjatw77.pdf

Noncoding RNAs regulate alternative splicing in Cancer.

Long noncoding RNAs (lncRNAs) constitute large portions of the mammalian transcriptome which appeared as a fundamental player, regulating various cellular mechanisms. LncRNAs do not encode proteins, have mRNA-like transcripts and frequently processed similar to the mRNAs. Many investigations have determined that lncRNAs interact with DNA, RNA molecules or proteins and play a significant regulatory function in several biological processes, such as genomic imprinting, epigenetic regulation, cell cycle regulation, apoptosis, and differentiation. LncRNAs can modulate gene expression on three levels: chromatin remodeling, transcription, and post-transcriptional processing. The majority of the identified lncRNAs seem to be transcribed by the RNA polymerase II. Recent evidence has illustrated that dysregulation of lncRNAs can lead to many human diseases, in particular, cancer. The aberrant expression of lncRNAs in malignancies contributes to the dysregulation of proliferation and differentiation process. Consequently, lncRNAs can be useful to the diagnosis, treatment, and prognosis, and have been characterized as potential cancer markers as well. In this review, we highlighted the role and molecular mechanisms of lncRNAs and their correlation with some of the cancers.

Long Non-Coding RNAs As Epigenetic Regulators in Cancer

Liver cancers cause a high rate of death worldwide and hepatocellular carcinoma (HCC) is considered as the most common primary liver cancer. HCC remains a challenging disease to treat. Wnt/β-catenin signaling pathway is considered a tumor-promoting factor in various cancers; hence, the present review focused on the role of Wnt signaling in HCC, and its association with progression and therapy response based on pre-clinical and clinical evidence. The nuclear translocation of β-catenin enhances expression level of genes such as c-Myc and MMPs in increasing cancer progression. The mutation of CTNNB1 gene encoding β-catenin and its overexpression can lead to HCC progression. β-catenin signaling enhances cancer stem cell features of HCC and promotes their growth rate. Furthermore, β-catenin prevents apoptosis in HCC cells and increases their migration via triggering EMT and upregulating MMP levels. It is suggested that β-catenin signaling participates in mediating drug resistance and immuno-resistance in HCC. Upstream mediators including ncRNAs can regulate β-catenin signaling in HCC. Anti-cancer agents inhibit β-catenin signaling and mediate its proteasomal degradation in HCC therapy. Furthermore, clinical studies have revealed the role of β-catenin and its gene mutation (CTNBB1) in HCC progression. Based on these subjects, future experiments can focus on developing novel therapeutics targeting Wnt/β-catenin signaling in HCC therapy.

/pdf/wnt-b-catenin-signaling-as-a-driver-of-hepatocellular-1ytp82zsup.pdf

Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways.

p53-targeted lncRNA ST7-AS1 acts as a tumour suppressor by interacting with PTBP1 to suppress the Wnt/β-catenin signalling pathway in glioma.

Plenty of reports have probed the involvement of abnormally expressed lncRNAs in multiple cancers, including lung squamous cell carcinoma (LUSC). Through online database GEPIA, lncRNA PITPNA antisense RNA 1 (PITPNA-AS1) was highly expressed in LUSC samples, and these tendency was further affirmed in LUSC cells. The aim of current study was to investigate the related mechanism of PITPNA-AS1 in LUSC. Functional experiments verified that depletion of PITPNA-AS1 hampered the proliferative and migratory abilities, but accelerated apoptosis of LUSC cells. Additionally, we observed the increased expression of HMGB3 and its positive correlation with PITPNA-AS1 in LUSC samples. Interestingly, PITPNA-AS1 mainly located in the cytosol of LUSC cells, and also affected mRNA stability of HMGB3. Furthermore, the repressed mRNA stability of HMGB3 by PITPNA-AS1 via TAF15 was exposed through mechanism experiments. The mediatory function of PITPNA-AS1 on HMGB3 was validated via rescue assays. All in all, PITPNA-AS1 promoted the proliferation and migration of LUSC cells via stabilizing HMGB3 by TAF15. In conclusion, our study displayed a novel mechanism underlying PITPNA-AS1 in LUSC cells.

LncRNA PITPNA-AS1 boosts the proliferation and migration of lung squamous cell carcinoma cells by recruiting TAF15 to stabilize HMGB3 mRNA.

Multifarious biological functions of long noncoding RNAs (lncRNAs) have been reported in various cancers including bladder cancer (BCa). This study aims to determine the biological role of a certain lncRNA in BCa. Consistent with the data of The Cancer Genome Atlas database, it was validated that lncRNA HLA complex group 22 (HCG22) was weakly expressed in BCa samples and lowly expressed HCG22 was closely correlated with low overall survival of the BCa patient. To verify the role of HCG22 in BCa progression, functional experiments were carried out in two representative BCa cells (J82 and T24) and the negative effects of HCG22 expression on the cell proliferation, migration, and epithelial-mesenchymal transition were identified. Mechanistically, polypyrimidine tract-binding protein 1 (PTBP1), which was highly expressed in BCa tissues and cell lines, was negatively regulated by HCG22 and the PTBP1-mediated Warburg effect was also obstructed by HCG22. Furthermore, HCG22 modulated the expression of PTBP1 through destabilizing human antigen R (HuR). And functional rescue assays confirmed that HCG22 functioned in bladder cancer through downregulating PTBP1. In conclusion, the present study revealed that HCG22 inhibited BCa progression via the HuR/PTBP1 axis, opening new prospects for potent therapeutic regimens for BCa patients.

Long noncoding RNA HCG22 suppresses proliferation and metastasis of bladder cancer cells by regulation of PTBP1.

Hepatocellular carcinoma (HCC) is a common malignant tumor in China. Advanced treatment like transcatheter hepatic arterial chemoembolization (TACE) has prolonged the lives of many HCC patients. However, the prognosis of most HCC patients remains unsatisfactory. Recently, circular RNAs (circRNAs) have been gradually unveiled to exert considerable functions in cancer. Promising circRNAs in HCC remains to be further elucidated. Gene expression was assessed by qRT-PCR and western blot. The function of circ-DENND4C in HCC was estimated by both in vitro and in vivo experiments. The location of circ-DENND4C in HCC cells was determined by subcellular fractionation and FISH assays. The association among molecules were analyzed through RNA pull down, RIP and luciferase reporter assays. circ-DENND4C (DENN domain containing 4C), an oncogene identified in breast cancer, was overexpressed in HCC cells. Also, circ-DENND4C exerted pro-tumor functions in HCC through activating Wnt/β-catenin pathway. Importantly, circ-DENND4C could augment transcription factor 4 (TCF4) expression to activate Wnt/β-catenin signaling via sequestering miR-195-5p. Moreover, following rescue assays disclosed that circ-DENND4C mediated malignant phenotypes in HCC cells via up-regulating TCF4 through sponging miR-195-5p. circ-DENND4C boosted TCF4 expression to modulate malignant behaviors of HCC cells via activating Wnt/β-catenin pathway, which might offer a promising target for HCC treatment.

/pdf/circ-dennd4c-up-regulates-tcf4-expression-to-modulate-4drkytmm34.pdf

Circ-DENND4C up-regulates TCF4 expression to modulate hepatocellular carcinoma cell proliferation and apoptosis via activating Wnt/β-catenin signal pathway

Background Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death worldwide. MicroRNAs (MiRNAs) have been reported to regulate cell functions through exosomes. Through the Gene Expression Omnibus (GEO) database, miR-620 was selected as a serum miRNA highly expressed in ESCC, but its detailed role in ESCC has not been explored. Tumor-secreted miRNAs have been reported to promote cancer metastasis through reprogramming the aerobic glycolysis of lung fibroblasts. Therefore, we intended to verify whether exosomal miR-620 secreted in ESCC cells may regulate the aerobic glycolysis of lung fibroblasts. Methods The effect of miR-620 on the aerobic glycolysis of ESCC cells was firstly verified through bioinformatics prediction and mechanism assays. Exosomes secreted from ESCC cells was detected, and the influence of exosomal miR-620 in regulating the aerobic glycolysis of lung fibroblasts was then verified both in vitro and in vivo. Results MiR-620 inhibited ESCC malignancy and suppressed the aerobic glycolysis of ESCC cells via targeting Forkhead box M1 (FOXM1) and human epidermal growth factor receptor 2 (HER2). Moreover, exosomal miR-620 was highly secreted in ESCC and could regulate HFL1 aerobic glycolysis via FOXM1/HER2 signaling. Furthermore, exosomal miR-620 could promote ESCC metastasis by reprogramming the aerobic glycolysis of lung fibroblasts (HFL1). Conclusion Exosomal miR-620 secreted by ESCC cells inhibited the aerobic glycolysis via FOXM1/HER2 axis and promoted cancer metastasis.

/pdf/cancer-secreted-exosomal-mir-620-inhibits-escc-aerobic-2aryecap.pdf

Cancer-Secreted Exosomal MiR-620 Inhibits ESCC Aerobic Glycolysis via FOXM1/HER2 Pathway and Promotes Metastasis

The process of bone regeneration is complicated, and it is still a major clinical challenge to regenerate critical-size bone defects caused by severe trauma, infection, and tumor resection. Intracellular metabolism has been found to play an important role in the cell fate decision of skeletal progenitor cells. GW9508, a potent agonist of the free fatty acid receptors GPR40 and GPR120, appears to have a dual effect of inhibiting osteoclastogenesis and promoting osteogenesis by regulating intracellular metabolism. Hence, in this study, GW9508 was loaded on a scaffold based on biomimetic construction principles to facilitate the bone regeneration process. Through 3D printing and ion crosslinking, hybrid inorganic-organic implantation scaffolds were obtained after integrating 3D-printed β-TCP/CaSiO3 scaffolds with a Col/Alg/HA hydrogel. The 3D-printed β-TCP/CaSiO3 scaffolds had an interconnected porous structure that simulated the porous structure and mineral microenvironment of bone, and the hydrogel network shared similar physicochemical properties with the extracellular matrix. The final osteogenic complex was obtained after GW9508 was loaded into the hybrid inorganic-organic scaffold. To investigate the biological effects of the obtained osteogenic complex, in vitro studies and a rat cranial critical-size bone defect model were utilized. Metabolomics analysis was conducted to explore the preliminary mechanism. The results showed that 50 μM GW9508 facilitated osteogenic differentiation by upregulating osteogenic genes, including Alp, Runx2, Osterix, and Spp1 in vitro. The GW9508-loaded osteogenic complex enhanced osteogenic protein secretion and facilitated new bone formation in vivo. Finally, the results from metabolomics analysis suggested that GW9508 promoted stem cell differentiation and bone formation through multiple intracellular metabolism pathways, including purine and pyrimidine metabolism, amino acid metabolism, glutathione metabolism, and taurine and hypotaurine metabolism. This study provides a new approach to address the challenge of critical-size bone defects.

/pdf/3d-printed-bioactive-scaffold-loaded-with-gw9508-promotes-lsq138mg.pdf

3D-Printed Bioactive Scaffold Loaded with GW9508 Promotes Critical-Size Bone Defect Repair by Regulating Intracellular Metabolism

Objective To clarify the application value of 5-hydroxymethylcytosine (5hmC) in evaluating the progression of chronic hepatitis B (CHB) to hepatocellular carcinoma (HCC) based on difference analysis. Methods A total of 180 patients were enrolled. Among them, 84 patients with chronic hepatitis B virus (HBV) infection while no progression to hepatocellular carcinoma (HCC) were included in the control group (CG), and 96 patients with HCC developed from HBV infection were included in the research group (RG). Two-thirds of the samples were used in the training set and 1/3 samples in the validation set to detect the level of 5hmC in both groups based on the modified nano-hmC-Seal technique. The expression levels of 5hmC-related genes TET2 and TET3 were quantified by qPCR, and the correlation between TET3 and 5hmC was analyzed by Pearson's correlation coefficients. Receiver operating characteristic (ROC) curves were drawn to evaluate the application value of the TET3-based 5hmC prediction model in the early diagnosis of HCC. Results (i) The expression of 5hmC in RG was lower than that in CG, no matter in the training set or the validation set. (ii) 5hmC was significantly enriched in the region between the transcription initiation site and the transcription end site but was depleted in the flanking region. (iii) 5hmC-related genes TET2 and TET3 were significantly downregulated in HCC patients, whether in the training set or the validation set. (iv) In both the training and validation sets, TET3 showed a positive association with 5hmC. (v) ROC analysis results showed that the 5hmC prediction model could be used to predict the progression of CHB to HCC (training set: AUC = 0.81, 0.729-0.893; validation set: AUC = 0.84, 0.739-0.936). Conclusions TET3 expression based on 5hmC sequencing is a landmark molecule for evaluating the progression of HCC in CHB patients, which is worthy of further study and promotion.

/pdf/value-of-5-hydroxymethylcytosine-in-hbv-carrying-high-risk-10qn3js6.pdf

Value of 5-Hydroxymethylcytosine in HBV-Carrying High-Risk Hepatocellular Carcinoma Population: An Evaluation Based on Differential Analysis

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