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

The paired‐like homeodomain transcription factor 2 (PITX2), a downstream effector of wnt/β‐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. What's new? There is an urgent need to identify novel biomarkers that are capable of predicting tumor response and survival outcome for chemoradiotherapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC). One such marker, reported for the first time here, may be the gene PITX2 (paired‐like homeodomain transcription factor 2). Increased expression of PITX2 was positively correlated with ESCC tumor aggressiveness, and its elevated expression was found to occur more frequently in CRT‐resistant than CRT‐sensitive disease. The results suggest that PITX2 expression could be used to evaluate tumor response to CRT and to optimize ESCC treatment strategies.