DNA polymerase iota (Pol ι) promotes invasion and metastasis of esophageal squamous cell carcinoma

Abstract

DNA polymerase iota (Pol ι) is an error-prone DNA polymerase involved in translesion DNA synthesis (TLS) that contributes to the accumulation of DNA mutations. We recently showed that Pol ι is overexpressed in human esophageal squamous cell cancer (ESCC) tissues which promotes ESCC' progression. The present study was aimed at investigating the molecular mechanisms by which Pol ι enhances the invasiveness and metastasis of ESCC cells. We found that the expression of Pol ι is significantly higher in ESCCs with lymph node metastasis compared to those without lymph node metastasis. Kaplan-Meier analysis revealed an inverse correlation between Pol ι expression and patient prognosis. The expression levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), two essential regulators of cells' invasiveness, were positively associated with Pol ι expression in ESCC tissues. Ectopic expression of Pol ι enhanced the motility and invasiveness of ESCC cells as evaluated by wound-healing and transwell assays, respectively. A xenograft nude mouse model showed that Pol ι promotes the colonization of ESCC cells in the liver, lung and kidney. Signaling pathway analysis identified the JNK-AP-1 cascade as a mediator of the Pol ι-induced increase in the expression of MMP-2/9 and enhancement of ESCC progression. These data demonstrate the underlying mechanism by which Pol ι promotes ESCC progression, suggesting that Pol ι is a potential novel prognostic biomarker and therapeutic target for ESCC.

Phosphorylation of ETS‐1 is a critical event in DNA polymerase iota‐induced invasion and metastasis of esophageal squamous cell carcinoma

“…(14,15) We also found that Pol ι promotes invasiveness and migration of ESCC cells in vitro. (15) However, the process of Pol ι-mediated invasion and metastasis of ESCC cells is not well understood. To explore the potential mechanisms responsible for Pol ι-mediated metastasis, RNA-Seq transcriptome analysis was performed using RNA isolated from Pol ι-knocking down and control ESCC cells.…”

“…Our previous work demonstrated that the expression level of Pol ι is closely associated with tumor progression and poor prognosis of ESCC . To confirm the correlated expression among Pol ι, ETS‐1 and ETS‐1 phosphorylation at threonine‐38, immunohistochemical staining was performed in 93 ESCC tissues.…”

“…Our previous work demonstrated that the expression level of Pol ι is closely associated with tumor progression and poor prognosis of ESCC. (15) To confirm the correlated expression among Pol ι, ETS-1 and ETS-1 phosphorylation at threonine-38, immunohistochemical staining was performed in 93 ESCC tissues. A significant positive correlation was observed between phosphorylation of ETS-1 and expression of Pol ι in these ESCC tissues, yet no correlation was evident between ETS-1 expression and Pol ι expression ( Fig.…”

“…Due to its error‐prone characters, ectopic expression of Pol ι may contribute to the accumulation of genomic mutation, carcinogenesis and tumor progression. Previously, we found that overexpression of Pol ι is associated with a metastatic and aggressive tumor phenotype in ESCC . However, the underlying mechanisms remain to be clarified.…”

“…Previously, we found that overexpression of Pol ι is associated with a metastatic and aggressive tumor phenotype in ESCC. (15) However, the underlying mechanisms remain to be clarified. In this study, using RNA-Seq transcriptome analysis, 718 genes were identified to be differentially expressed between Pol ι-knocking down and control ESCC cells.…”