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.
Highlights
Esophageal cancer is the sixth most common cause of cancer-related death worldwide [1]
Our results revealed that the expression of Pol ι is significantly higher in esophageal squamous cell cancer (ESCC) with lymph node metastasis than those without lymph node metastasis (p0.05, Figure 1C)
We examined the expression of Pol ι and its association with tumor metastasis in 82 samples of ESCC
Summary
Esophageal cancer is the sixth most common cause of cancer-related death worldwide [1]. Esophageal squamous cell carcinoma (ESCC) is the major histological type of esophageal cancer (>90%) in China and accounts for 60-70% of esophageal cancer cases worldwide [2, 3]. Cancer metastasis is a complex multi-step process involving in uncontrolled proliferation, migration, invasion, adhesion and angiogenesis [5]. The lymph node invasion is considered one of the most important indicators for poor prognosis of ESCC patients [8, 9]. A number of molecular alterations have been identified, the mechanism by which cancer cells invade to lymph nodes has not been fully elucidated
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