PITX2: A promising predictive biomarker of patients' prognosis and chemoradioresistance in esophageal squamous cell carcinoma

Abstract

The paired-like homeodomain transcription factor 2 (PITX2), a downstream effector of wnt/b-catenin signaling, is well known to play critical role during normal embryonic development. However, the possible involvement of PITX2 in human tumorigenesis remains unclear. In this study, we extend its function in human esophageal squamous cell carcinoma (ESCC). The real-time PCR, Western blotting and immunohistochemistry (IHC) methods were applied to examine expression pattern of PITX2 in two different cohorts of ESCC cases treated with definitive chemoradiotherapy (CRT). Receiver operating characteristic (ROC) curve analysis was used to determine the cutoff point for PITX2 high expression in the training cohort. The ROC-derived cutoff point was then subjected to analyze the association of PITX2 expression with patients' survival and clinical characteristics in training and validation cohort, respectively. The expression level of PITX2 was significantly higher in ESCCs than that in normal esophageal mucosa. There was a positive correlation between PITX2 expression and clinical aggressiveness of ESCC. Importantly, high expression of PITX2 was observed more frequently in CRT resistant group than that in CRT effective group (p < 0.05). Furthermore, high expression of PITX2 was associated with poor disease-specific survival (p < 0.05) in ESCC. Then, the MTS, clonogenic survival fraction and cell apoptosis experiments showed that knockdown of PITX2 substantially increased ESCC cells sensitivity to ionizing radiation (IR) or cisplatin in vitro. Thus, the expression of PITX2, as detected by IHC, may be a useful tool for predicting CRT resistance and serves as an independent molecular marker for poor prognosis of ESCC patients treated with definite CRT.Esophageal squamous cell carcinoma (ESCC) is one of the most common incident cancers, which accounts for a significant number of cancer-related deaths in worldwide. 1,2 Recently, for those thoracic cases with locally advanced disease, definitive chemoradiotherapy (CRT) is an important component of the therapeutic strategy. 3,4 Even if the great achievement has accomplished in diagnostic development and radiotherapy advance, the overall 5-year survival rate of ESCC patients is still unsatisfactory. [5][6][7] The high rate of recurrence and metastasis is closely related with the inferior quality of survival outcome. Currently, only the stage based on tumor node metastases classification and primary complete response (CR) to CRT are widely accepted as prognostic factors. However, the clinical responses of ESCC to CRT are various, and the survival rate between patients with the same clinical stage and/or CRT response is quite different. 8,9 Therefore, there is still an urgent need to identify novel promising markers that could precisely predict tumor response to CRT and further stratify ESCC patient survival outcome.The paired-like homeodomain transcription factor 2 (PITX2) gene, located in chromosome 4q25-a27, encodes a transcription factor of the paired-like homeodomain protein fam...

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

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FRAT1 expression regulates proliferation in colon cancer cells

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Diagnostic and predictive significance of serum microRNA-7 in esophageal squamous cell carcinoma

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