Serine rich splicing factor 3 (SRSF3) plays a critical role in liver function and its loss promotes chronic liver damage and regeneration. As a consequence, genetic deletion of SRSF3 in hepatocytes caused progressive liver disease and ultimately led to hepatocellular carcinoma. Here we show that SRSF3 is decreased in human liver samples with non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or cirrhosis that was associated with alterations in RNA splicing of known SRSF3 target genes. Hepatic SRSF3 expression was similarly decreased and RNA splicing dysregulated in mouse models of NAFLD and NASH. We showed that palmitic acid-induced oxidative stress caused conjugation of the ubiquitin like NEDD8 protein to SRSF3 and proteasome mediated degradation. SRSF3 was selectively neddylated at lysine11 and mutation of this residue (SRSF3-K11R) was sufficient to prevent both SRSF3 degradation and alterations in RNA splicing. Finally prevention of SRSF3 degradation in vivo partially protected mice from hepatic steatosis, fibrosis and inflammation. These results highlight a neddylation-dependent mechanism regulating gene expression in the liver that is disrupted in early metabolic liver disease and may contribute to the progression to NASH, cirrhosis and ultimately hepatocellular carcinoma.

/pdf/degradation-of-splicing-factor-srsf3-contributes-to-53e2ioc7xw.pdf

Degradation of splicing factor SRSF3 contributes to progressive liver disease

A large number of studies have focused on identifying molecular biomarkers, including microRNAs (miRNAs) to aid in the diagnosis and prognosis of the most common subtypes of non-Hodgkin lymphoma (NHL), Diffuse Large B-cell Lymphoma and Follicular Lymphoma. NHL is difficult to diagnose and treat with many cases becoming resistant to chemotherapy, hence the need to identify improved biomarkers to aid in both diagnosis and treatment modalities. This review summarises more recent research on the dysregulated miRNA expression profiles found in NHL, as well as the regulatory role and biomarker potential of cellular and circulating miRNAs found in tissue and serum, respectively. In addition, the emerging field of research focusing on miRNA single nucleotide polymorphisms (miRSNPs) in genes of the miRNA biogenesis pathway, in miRNA genes themselves, and in their target sites may provide new insights on gene expression changes in these genes. These miRSNPs may impact miRNA networks and have been shown to play a role in a host of different cancer types including haematological malignancies. With respect to NHL, a number of SNPs in miRNA-binding sites in target genes have been shown to be associated with overall survival.

https://www.mdpi.com/2073-4425/7/12/130/pdf

Dysregulated MicroRNA Expression Profiles and Potential Cellular, Circulating and Polymorphic Biomarkers in Non-Hodgkin Lymphoma.

A functional variant at miRNA-122 binding site in IL-1α 3′ UTR predicts risk and HPV-positive tumours of oropharyngeal cancer

A large number of studies have focused on identifying molecular biomarkers, including microRNAs (miRNAs) to aid in the diagnosis and prognosis of the most common subtypes of non-Hodgkin lymphoma (NHL), Diffuse Large B-cell Lymphoma and Follicular Lymphoma NHL is difficult to diagnose and treat with many cases becoming resistant to chemotherapy, hence the need to identify improved biomarkers to aid in both diagnosis and treatment modalities This review summarises more recent research on the dysregulated miRNA expression profiles found in NHL, as well as the regulatory role and biomarker potential of cellular and circulating miRNAs found in tissue and serum, respectively In addition, the emerging field of research focusing on miRNA single nucleotide polymorphisms (miRSNPs) in genes of the miRNA biogenesis pathway, in miRNA genes themselves, and in their target sites may provide new insights on gene expression changes in these genes These miRSNPs may impact miRNA networks and have been shown to play a role in a host of different cancer types including haematological malignancies With respect to NHL, a number of SNPs in miRNA-binding sites in target genes have been shown to be associated with overall survival

Dysregulated microRNA expression profiles and potential cellular, circulating and polymorphic biomarkers in Non-Hodgkin Lymphoma

Protein tyrosine kinase 6 (PTK6) is a nonreceptor tyrosine kinase that plays a crucial role in some tumors. However, the role of PTK6 is still unknown in hepatocellular carcinoma (HCC). In this study, we demonstrated that the PTK6 expression was upregulated in HCC tissues compared with adjacent normal tissues. Moreover, PTK6 was upregulated in the HCC cell lines (Bel7402, Hep3B, SMMC7721 and HepG2) compared with the normal liver epithelial cell line (THLE3). Ectopic expression of PTK6 promoted SMMC7721 cell proliferation, colony formation and invasion. Moreover, inhibition PTK6 expression suppressed the SMMC7721 cell proliferation, colony formation and invasion. Overexpression of PTK6 suppressed ERK1/2 phosphorylated expression. These data suggested that PTK6 played an oncogene role in the development of HCC.

PTK6 promotes hepatocellular carcinoma cell proliferation and invasion.

Polymorphisms in pre-miRNAs may affect its expression, then have effect on its target mRNAs and be associated with cancer susceptibility. In this study, we evaluated the association of an indel polymorphism rs57408770 in pre-miR-3131 with hepatocellular carcinoma (HCC) susceptibility in a Chinese population. The contribution of rs57408770 to HCC risk was investigated in two independent case-control sets (1051 HCC and 1058 controls). Logistic regression analysis showed that the insertion allele of rs57408770 was significantly associated with an increased risk for HCC occurrence in both case-control studies. Moreover, the results of genotype-phenotype correlation analysis from both in vivo and in vitro experiments showed that the insertion allele was significantly correlated with higher expression of mature miR-3131 comparing with the deletion allele. The RNA-Binding Protein Immunoprecipitation assay results indicated that rs57408770 could affect the expression level of mature miR-3131 probably through disturbing the binding of splicing factor SRp20 with pre-miR-3131. Furthermore, overexpression of miR-3131 displayed a proliferation promoting and anti-apoptosis effect on HCC cell lines, suggesting that miR-3131 may act as a proto-oncogene in HCC. Finally, human genome-wide gene expression profile assay was used to screen the targets of miR-3131. The overexpressed miR-3131 could lead to a significant decrease of DTHD1 and XAF1 mRNA level. Taken together, our findings provided evidence that rs57408770 may play a functional role in the carcinogenesis of HCC by affecting SRp20 binding with pre-miR-3131 and affecting the expression of mature miR-3131, subsequently affecting the expression of DTHD1 and XAF1, thus confers risk for HCC.

An indel polymorphism within pre-miR3131 confers risk for hepatocellular carcinoma.

Introduction Single-cell transcriptome sequencing (ScRNA-seq) has emerged as an effective method for examining cell differentiation and development. In non-model plants, it hasn't been employed very much, especially in sink organs that are abundant in secondary metabolites. Results In this study, we sequenced the single-cell transcriptomes at two developmental phases of cassava tuberous roots using the technology known as 10x Genomics (S1, S2). In total, 14,566 cells were grouped into 15 different cell types, primarily based on the marker genes of model plants known to exist. In the pseudotime study, the cell differentiation trajectory was defined, and the difference in gene expression between the two stages on the pseudotime axis was compared. The differentiation process of the vascular tissue and cerebral tissue was identified by the trajectory. We discovered the rare cell type known as the casparian strip via the use of up-regulated genes and pseudotime analysis, and we explained how it differentiates from endodermis. The successful creation of a protoplast isolation technique for organs rich in starch was also described in our study. Discussion Together, we created the first high-resolution single-cell transcriptome atlas of cassava tuberous roots, which made significant advancements in our understanding of how these roots differentiate and develop.

/pdf/single-cell-transcriptome-sequencing-atlas-of-cassava-1xsrtuvb.pdf

Single-cell transcriptome sequencing atlas of cassava tuberous root

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, and multiple host genetic factors are believed to contribute to HCC development. The small G protein signaling modulator 3 (SGSM3) has been shown to be associated with small G protein coupled receptor signal transduction pathway, suggesting a potential role in HCC susceptibility. We carried out a case–control study in a Chinese population (502 cases and 513 controls) to determine whether the 4-bp insertion/deletion polymorphism (rs56228771) in 3′ untranslated region of SGSM3 could affect HCC susceptibility. Logistic regression analysis showed that compared with the del/del genotype, the ins/del genotype of rs56228771 was associated with a significantly decreased risk of HCC [adjusted odd ratio = 0.55, 95 % confidence interval (CI) = 0.42–0.73, P = 1.93 × 10−5]. The combined ins/del + ins/ins genotypes contributed to a 45 % decreased HCC risk (95 % CI = 0.42–0.73, P = 1.03 × 10−5). This protective trend was more prominent in the HBsAg-negative subgroup. Furthermore, in vivo experiments showed that mRNA levels of SGSM3 from HCC tumor tissues and adjacent non-HCC tissues were correlated with rs56228771 genotypes. Tissue samples with ins/ins genotype have the highest level of SGSM3, which are 2.85–3.00-fold and 1.46–1.57-fold higher than that with ins/del and del/del genotype, respectively. Similar results were also observed with four common hepatoma cell lines in vitro. In addition, compared with HCC tissues, significantly higher SGSM3 expression was observed in adjacent non-HCC tissues (fold change = 2.48), implying its tumor suppressor roles in HCC. Bioinformatics prediction showed that the insertion allele disrupted a binding site for microRNA (miRNA)-151-5p, which would upregulate SGSM3. Taken together, we provided initial evidence that rs56228771 may contribute to hepatocarcinogenesis, possibly by affecting SGSM3 expression through a miRNA-mediated regulation. The replication of our studies in other populations and functional analysis will further strengthen the underlining mechanism.

Association between an insertion/deletion polymorphism within 3'UTR of SGSM3 and risk of hepatocellular carcinoma.

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An indel polymorphism within pre-miR3131 confers risk for hepatocellular carcinoma.

Single-cell transcriptome sequencing atlas of cassava tuberous root

Association between an insertion/deletion polymorphism within 3'UTR of SGSM3 and risk of hepatocellular carcinoma.