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Most solid tumors become stiff with progression of cancer. Cancer Associated Fibroblasts (CAFs), most abundant stromal cells in the tumor microenvironment (TME), are known to mediate such stiffening. While the biochemical crosstalk between CAFs and cancer cells have been widely investigated, it is not clear if and how CAFs in stiffer TME promote metastatic progression. To gather insights into the process, we controlled the mechanical stiffness of the substrates and collected gene expression data with human colorectal CAFs. We cultured human primary CAFs on 2D polyacrylamide hydrogels with increasing elastic modulus (E) of 1, 10 and 40 kPa, and performed genome-wide transcriptome analyses in these cells to identify expression levels of ~16000 genes. The high-quality RNAseq results can be an excellent data-source for bioinformatic analysis for identifying novel pathways and biomarkers in cancer development and metastatic progression. With thorough analysis and accurate interpretation, this data may help researchers understand the role of mechanical stiffness of the TME in CAF-cancer cell crosstalk.

 

In eukaryotes, the origin recognition complex (ORC) is required for the initiation of DNA replication. The smallest subunit of ORC, Orc6, is essential for prereplication complex (pre-RC) assembly and cell viability in yeast and for cytokinesis in metazoans. However, unlike other ORC components, the role of human Orc6 in replication remains to be resolved. Here, we identify an unexpected role for hOrc6, which is to promote S-phase progression after pre-RC assembly and DNA damage response. Orc6 localizes at the replication fork and is an accessory factor of the mismatch repair (MMR) complex. In response to oxidative damage during S phase, often repaired by MMR, Orc6 facilitates MMR complex assembly and activity, without which the checkpoint signaling is abrogated. Mechanistically, Orc6 directly binds to MutSα and enhances the chromatin-association of MutLα, thus enabling efficient MMR. Based on this, we conclude that hOrc6 plays a fundamental role in genome surveillance during S phase. 

Cell cycle is a cellular process that is subject to stringent control. In contrast to the wealth of knowledge of proteins controlling the cell cycle, very little is known about the molecular role of lncRNAs (long noncoding RNAs) in cell-cycle progression. By performing genome-wide transcriptome analyses in cell-cycle-synchronized cells, we observed cell-cycle phase-specific induction of >2000 lncRNAs. Further, we demonstrate that an S-phase-upregulated lncRNA, SUNO1 , facilitates cell-cycle progression by promoting YAP1-mediated gene expression. SUNO1 facilitates the cell-cycle-specific transcription of WTIP , a positive regulator of YAP1, by promoting the co-activator, DDX5-mediated stabilization of RNA polymerase II on chromatin. Finally, elevated SUNO1 levels are associated with poor cancer prognosis and tumorigenicity, implying its pro-survival role. Thus, we demonstrate the role of a S-phase up-regulated lncRNA in cell-cycle progression via modulating the expression of genes controlling cell proliferation. 

Long noncoding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides that do not code for proteins. LncRNAs play crucial regulatory roles in several biological processes via diverse mechanisms and their aberrant expression is associated with various diseases. LncRNA genes are further subcategorized based on their relative organization in the genome. MicroRNA (miRNA)‐host‐gene‐derived lncRNAs (lnc‐MIRHGs) refer to lncRNAs whose genes also harbor miRNAs. There exists crosstalk between the processing of lnc‐MIRHGs and the biogenesis of the encoded miRNAs. Although the functions of the encoded miRNAs are usually well understood, whether those lnc‐MIRHGs play independent functions are not fully elucidated. Here, we review our current understanding of lnc‐MIRHGs, including their biogenesis, function, and mechanism of action, with a focus on discussing the miRNA‐independent functions of lnc‐MIRHGs, including their involvement in cancer. Our current understanding of lnc‐MIRHGsstrongly indicates that this class of lncRNAs could play important roles in basic cellular events as well as in diseases.

This article is categorized under:

Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs