HNRNPLL stabilizes mRNA for DNA replication proteins and promotes cell cycle progression in colorectal cancer cells

Abstract

Heterogeneous nuclear ribonucleoprotein L‐like (HNRNPLL), an RNA‐binding protein that regulates alternative splicing of pre‐mRNA, has been shown to regulate differentiation of lymphocytes, as well as metastasis of colorectal cancer cells. Here, we show that HNRNPLL promotes cell cycle progression and, hence, proliferation of colorectal cancer cells. Functional annotation analysis of those genes whose expression levels were changed threefold or more in RNA sequencing analysis between SW480 cells overexpressing HNRNPLL and those knocked down for HNRNPLL revealed enrichment of DNA replication‐related genes by HNRNPLL overexpression. Among 13 genes detected in the DNA replication pathway, PCNA,RFC3 and FEN1 showed reproducible upregulation by HNRNPLL overexpression both at mRNA and at protein levels in SW480 and HT29 cells. Importantly, knockdown of any of these genes alone suppressed the proliferation‐promoting effect induced by HNRNPLL overexpression. RNA‐immunoprecipitation assay presented a binding of FLAG‐tagged HNRNPLL to mRNA of these genes, and HNRNPLL overexpression significantly suppressed the downregulation of these genes during 12 h of actinomycin D treatment, suggesting a role of HNRNPLL in mRNA stability. Finally, analysis of a public RNA sequencing dataset of clinical samples suggested a link between overexpression of HNRNPLL and that of PCNA,RFC3 and FEN1. This link was further supported by immunohistochemistry of colorectal cancer clinical samples, whereas expression of CDKN1A, which is known to inhibit the cooperative function of PCNA, RFC3 and FEN1, was negatively associated with HNRNPLL expression. These results indicate that HNRNPLL stabilizes mRNA encoding regulators of DNA replication and promotes colorectal cancer cell proliferation.

Upregulation of FEN1 Is Associated with the Tumor Progression and Prognosis of Hepatocellular Carcinoma

“…Numerous studies have described the role played by FEN1 in tumor formation and proliferation. This gene has been reported to be upregulated in many human malignancies including non-small-cell lung cancer [16], breast cancer [17], prostate cancer [18], gastric cancer [19], colorectal cancer [20], and cervical cancer [21]. In the current study, we detected a higher expression of FEN1 in hepatocellular carcinoma tissues relative to adjacent nontumor tissues.…”

MYB mediates downregulation of the colorectal cancer metastasis suppressor heterogeneous nuclear ribonucleoprotein L‐like during epithelial‐mesenchymal transition

“…Our study demonstrated that heterogeneous nuclear ribonucleoprotein L‐like (HNRNPLL) is downregulated at the transcript level in CRC cells during epithelial‐mesenchymal transition (EMT), a critical event in the early step of cancer metastasis, 5,6 and that the downregulation modulates the alternative splicing of CD44 variable exons leading to increased expression of the CD44v6 isoform, which enhances the invasion activity through an interaction with the hepatocyte growth factor receptor 2 . In contrast, mesenchymal‐epithelial transition (MET) restores HNRNPLL, which then contributes to proliferation of CRC cells through increased expression of DNA replication factors, PCNA, RFC3, and FEN1, by binding to and stabilizing their pre‐mRNAs 7 . This intriguing fluctuation of HNRNPLL expression during EMT and MET has prompted us to elucidate the underlying molecular mechanisms.…”

Landscape of Alternative Splicing Events Related to Prognosis and Immune Infiltration in Glioma: A Data Analysis and Basic Verification

“…These key SF genes were significantly related to the infiltration of immune cells in the tumor microenvironment. These factors exert vital roles in the genesis and development of multiple tumors [11,[21][22][23][24][25][26][27][28][29][30][31][32].…”