Abstract
The expression of legumain which has been shown overexpressed in patients with metastatic gastric cancer is positively correlated to both disease progression and outcome, and negatively correlated to microRNA (miR)−3978 expression. The RNA-binding protein, poly r(C) binding protein 1 (PCBP1) was the most downregulated protein in the metastatic tissue specimens. Quantitative real-time PCR showed that PCBP1 expression is transcriptionally downregulated in peritoneal metastasis tissues. RNA immunoprecipitation experiments showed that PCBP1 and miR-3978 are sequestered in normal peritoneal tissue, but the complex is disrupted following metastatic progression. PCBP1 expression mimicked miR-3978 expression across gastric cancer patients. Finally, replenishment of PCBP1 or miR-3978 expression in the peritoneal metastasis cell line MKN45 decreased legumain protein expression and chemosensitized the cells to treatment with docetaxel. However, replenishment of one and concomitant depletion of the other failed to induce chemosensitivity to docetaxel. Replenishment of miR-3978 also resulted in induction of PCBP1 protein expression, potentially indicating that miR-3978 expression might downregulate a negative regulator targeting PCBP1. Our current study reveals PCBP1 as an additional biomarker in peritoneal metastasis. PCBP1 and miR-3978 expression were correlated and suggests a potential interplay of differential miRNA biogenesis and RNA binding protein during metastatic progression.
Highlights
The expression of legumain which has been shown overexpressed in patients with metastatic gastric cancer is positively correlated to both disease progression and outcome, and negatively correlated to microRNA−3978 expression
Our findings in the current study cumulatively indicate that the RNA binding protein, poly r(C) binding protein 1 (PCBP1) or heterogeneous nuclear ribonucleoprotein E1 expression correlates withmiR-3978 expression and that hnRNP E1 itself functions as a suppressor of tumor progression
Mass spectrometry analysis of protein expression from tissues obtained from patients with metastatic gastric cancer and tumor adjacent normal tissue revealed that whereas five proteins (PCBP1, DSP, FZD7, ITGA5, and MMP2) were downregulated at least 3 folds, four proteins (IGFBP4, KRT19, NODAL, and PRP4A1) were upregulated at least 3 folds in metastatic tumor tissue specimens compared to control tissue specimens
Summary
The expression of legumain which has been shown overexpressed in patients with metastatic gastric cancer is positively correlated to both disease progression and outcome, and negatively correlated to microRNA (miR)−3978 expression. PCBP1 and miR-3978 expression were correlated and suggests a potential interplay of differential miRNA biogenesis and RNA binding protein during metastatic progression. Given that legumain has been shown to be overexpressed in different metastatic cancers[13,14,15,16,25,26,27], it is imperative to define precise mechanism that regulates miR-3978 expression in gastric cancer patients with peritoneal metastasis. Our findings in the current study cumulatively indicate that the RNA binding protein, poly r(C) binding protein 1 (PCBP1) or heterogeneous nuclear ribonucleoprotein E1 (hnRNPE1) expression correlates withmiR-3978 expression and that hnRNP E1 itself functions as a suppressor of tumor progression
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