Non-alcoholic fatty liver disease (NAFLD) is becoming the most important risk factor for hepatocellular carcinoma (HCC). Understanding the progression of benign diseases to HCC is crucial for early prevention and reversal of malignant transformation. Alternative splicing (AS) of RNA plays a role in the pathogenicity, initiation, and transformation of liver disease. We summarize the changes or mutations in the activity of splicing factors in NAFLD and HCC, as well as the impact of AS mediated by epigenetic modifications such as DNA methylation, RNA methylation, histone modification, and protein phosphorylation on liver cell fate. We also summarize therapeutic methods and drugs that are helpful for treating NAFLD, HCC, and the early stages of NAFLD progression to HCC. 

Alternative splicing: a bridge connecting NAFLD and HCC.

Objective We previously elucidated that long non-coding RNA Promoter of CDKN1A Antisense DNA damage Activated RNA (PANDAR) as a p53-dependent oncogene to promote cisplatin resistance in ovarian cancer (OC). Intriguingly, high level of p53-independent PANDAR was found in cisplatin-resistant patients with p53 mutation. Here, our study probed the new roles and the underlying mechanisms of PANDAR in p53-mutant OC cisplatin-resistance. Methods A2780 and A2780-DDP cells were served as OC cisplatin-sensitive and cisplatin-resistant cells. HO-8910PM cells were subjected to construct chemotherapy-induced extracellular vesicles (Chemo-EVs). Transmission electron microscopy (TEM) and nanoparticle tracking analysis were employed to evaluate Chemo-EVs. Cell viability was assessed using cell counting kit-8 and colony formation assays. Cell apoptosis was assessed using Annexin V and propidium iodide staining. The relationships between PANDAR, serine and arginine-rich pre-mRNA splicing factor 9 (SRSF9) were verified by RNA immunoprecipitation and fluorescence in situ hybridization. Tumor xenograft experiment was employed to evaluate the effects of PANDAR-Chemo-EVs on OC cisplatin-resistance in vivo. Immunofluorescent staining and immunohistochemistry were performed in tumor tissue. Results PANDAR level increased in OC patients with p53-mutation. PANDAR efflux enacted via exosomes under cisplatin conditions. Additionally, exosomes from OC cell lines carried PANDAR, which significantly increased cell survival and chemoresistance in vitro and tumor progression and metastasis in vivo. During cisplatin-induced stress, SRSF9 was recruited to nuclear bodies by increased PANDAR and muted apoptosis in response to cisplatin. Besides, SRSF9 significantly increased the ratio of SIRT4/SIRT6 mRNA in OC. Conclusion Cisplatin-induced exosomes transfer PANDAR and lead to a rapid adaptation of OC cell survival through accumulating SRSF9 following cisplatin stress exposure.

Cisplatin-induced PANDAR-Chemo-EVs contribute to a more aggressive and chemoresistant ovarian cancer phenotype through the SRSF9-SIRT4/SIRT6 axis

Prostate cancer (PCa) is a prevalent cause of morbidity and mortality. DHRS2-modified human umbilical cord mesenchymal stem cells-derived exosomes (hUC-MSCs-derived exos) function in PCa. We explored the mechanism of DHRS2-modified hUC-MSCs-derived exos in PCa cell malignant behaviors. DHRS2 expression levels in WPMY-1 cells and 4 PCa cell lines were detected by RT-qPCR and Western blot. 22Rv1/DU145 cells with high/low DHRS2 expression were selected to establish the low/high DHRS2 expression models by transfection. Cell proliferation and apoptosis were detected by CCK-8, colony formation assays, and flow cytometry. hUC-MSCs were identified by oil red O, alizarin staining, and flow cytometry. Exos were extracted from hUC-MSCs by ultracentrifugation and identified by transmission electron microscopy, Nano series-Nano-ZS, and Western blot. DU145 cells were selected for in vitro study to further study the effects of DHRS2-modified exos on cell proliferation and apoptosis. The effect of DHRS2-modified exos on cell cycle distribution was detected by flow cytometry. DHRS2 was repressed in PCa cells. DHRS2 overexpression suppressed PCa cell proliferation and promoted apoptosis. Exos were successfully isolated from hUC-MSC. DHRS2-modified hUC-MSCs-derived exos carried DHRS2 into PCa cells and blocked malignant behaviors. Briefly, DHRS2 was repressed in PCa cells. DHRS2-modified hUC-MSCs-derived exos blocked PCa cell proliferation and enhanced apoptosis. 

Regulatory mechanism of DHRS2-modified human umbilical cord mesenchymal stem cells-derived exosomes in prostate cancer cell proliferation and apoptosis.

Inflammatory bowel disease (IBD) is an immune system disorder primarily characterized by colitis, the exact etiology of which remains unclear. Traditional treatment approaches currently yield limited efficacy and are associated with significant side effects. Extensive research has indicated the potent therapeutic effects of probiotics, particularly Lactobacillus strains, in managing colitis. However, the mechanisms through which Lactobacillus strains ameliorate colitis require further exploration. In our study, we selected Lactobacillus gasseri ATCC33323 from the intestinal microbiota to elucidate the specific mechanisms involved in modulation of colitis. Experimental findings in a DSS-induced colitis mouse model revealed that L. gasseri ATCC33323 significantly improved physiological damage in colitic mice, reduced the severity of colonic inflammation, decreased the production of inflammatory factors, and preserved the integrity of the intestinal epithelial structure and function. It also maintained the expression and localization of adhesive proteins while improving intestinal barrier permeability and restoring dysbiosis in the gut microbiota. E-cadherin, a critical adhesive protein, plays a pivotal role in this protective mechanism. Knocking down E-cadherin expression within the mouse intestinal tract significantly attenuated the ability of L. gasseri ATCC33323 to regulate colitis, thus confirming its protective role through E-cadherin. Finally, transcriptional analysis and in vitro experiments revealed that L. gasseri ATCC33323 regulates CDH1 transcription by affecting NR1I3, thereby promoting E-cadherin expression. These findings contribute to a better understanding of the specific mechanisms by which Lactobacillus strains alleviate colitis, offering new insights for the potential use of L. gasseri as an alternative therapy for IBD, particularly in dietary supplementation. 

Lactobacillus gasseri ATCC33323 affects the intestinal mucosal barrier to ameliorate DSS-induced colitis through the NR1I3-mediated regulation of E-cadherin

Profiling bovine blastocyst transcriptome at the single-cell level has enabled us to reveal the first cell lineage segregation, during which the inner cell mass (ICM), trophectoderm (TE), and an undefined population of transitional cells were identified. By comparing the transcriptome of blastocysts derived in vivo (IVV), in vitro from a conventional culture medium (IVC), and in vitro from an optimized reduced nutrient culture medium (IVR), we found a delay of the cell fate commitment to ICM in the IVC and IVR embryos. Developmental potential differences between IVV, IVC, and IVR embryos were mainly contributed by ICM and transitional cells. Pathway analysis of these non-TE cells between groups revealed highly active metabolic and biosynthetic processes, reduced cellular signaling, and reduced transmembrane transport activities in IVC embryos that may lead to reduced developmental potential. IVR embryos had lower activities in metabolic and biosynthetic processes but increased cellular signaling and transmembrane transport, suggesting these cellular mechanisms may contribute to improved blastocyst development compared to IVC embryos. However, the IVR embryos had compromised development compared to IVV embryos with notably over-active transmembrane transport activities that impaired ion homeostasis. 

In vitro culture alters cell lineage composition and cellular metabolism of bovine blastocyst

Abstract Background Serine and arginine-rich splicing factor 9 ( SRSF9) has been linked to the occurrence and progression of various cancers; however, its effects and mechanism of action hepatocellular carcinoma (HCC) have not been reported. In this study, we used a bioinformatics approach and in vitro assays to evaluate the expression of SRSF9 in HCC, its prognostic value, and its underlying regulatory mechanisms, including analyses of related pathways and the role of methylation. Methods Transcriptomic and DNA methylation data for 357 HCC cases and 50 paratumor tissues in The Cancer Genome Atlas database were obtained. Additionally, protein expression data for cell lines and tissue samples were obtained from the Human Protein Atlas. The CMap databased was used to predict candidate drugs targeting SRSF9. Various cell lines were used for in vitro validation. Results SRSF9 expression was significantly elevated in HCC and was negatively regulated by its methylation site cg06116271. The low expression of SRSF9 and hypermethylation of cg06116271 were both associated with a longer overall survival time. A correlation analysis revealed ten genes that were co-expressed with SRSF9 ; levels of CDK4 , RAN , DENR , RNF34, and ANAPC5 were positively correlated and levels of RBP4 , APOC1 , MASP2 , HP, and HPX were negatively correlated with SRSF9 expression. The knockdown of SRSF9 in vitro inhibited the proliferation and migration of HCC cells and significantly reduced the expression of proteins in the Wnt signaling pathway (DVL2 and β-catenin) and cell cycle pathway (Cyclin D and Cyclin E). A CMap analysis identified two drugs, camptothecin and apigenin, able to target and inhibit the expression of SRSF9 . Conclusions This study expands our understanding of the molecular biological functions of SRSF9 and cg06116271 and provides candidate diagnostic and therapeutic targets for HCC. 

/pdf/high-expression-of-serine-and-arginine-rich-splicing-factor-3gcuos5m.pdf

High expression of serine and arginine-rich splicing factor 9 (SRSF9) is associated with hepatocellular carcinoma progression and a poor prognosis

/pdf/high-expression-of-serine-and-arginine-rich-splicing-factor-lgt1dcup.pdf

Colorectal cancer is one of the most common malignant tumors in the digestive system. Traditional diagnosis and treatment methods have not significantly improved the overall survival of patients. In this study, we explored the value of ATP2A1 as a biomarker in predicting the prognosis of colorectal cancer patients. We used the TCGA database to reveal the relationship between ATP2A1 mRNA level and prognosis, methylation, and immune invasion in colorectal cancer. The results showed that the expression of ATP2A1 was increased in colorectal cancer. The overall survival of patients with high expression of ATP2A1 was significantly lower than patients with low expression of ATP2A1. Cox regression analysis showed that high expression of ATP2A1 was an independent risk factor for poor prognosis in colorectal cancer patients. In addition, we used three datasets to perform a meta-analysis, which further confirmed the reliability of the results. Furthermore, we revealed that ATP2A1 could significantly inhibit the proliferation of colorectal cancer cells by inhibiting the autophagy process and was associated with several immune cells, especially CD8 + T cells. Finally, four small molecule drugs with potential inhibition of ATP2A1 expression were found by CMap analysis. This study demonstrates for the first time that ATP2A1 is a potential pathogenic factor, which may play a significant role in colorectal cancer.

https://www.frontiersin.org/articles/10.3389/fgene.2022.661348/pdf

Increased ATP2A1 Predicts Poor Prognosis in Patients With Colorectal Carcinoma

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High expression of serine and arginine-rich splicing factor 9 (SRSF9) is associated with hepatocellular carcinoma progression and a poor prognosis

High expression of serine and arginine-rich splicing factor 9 (SRSF9) is associated with hepatocellular carcinoma progression and a poor prognosis

Increased ATP2A1 Predicts Poor Prognosis in Patients With Colorectal Carcinoma