title: 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/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.
authors.affiliation: Department of Radiotherapy, the First Affiliated Hospital, Anhui Medical University, Hefei, China.
authors.forename: Jia-Xing
authors.initials: JX
authors.lastname: Zhang
authors.forename: Zhu-Ting
authors.initials: ZT
authors.lastname: Tong
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Chai
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Ming-Ran
authors.initials: MR
authors.lastname: Xie
authors.forename: An-Li
authors.initials: AL
authors.lastname: Zhang
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Wu
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.forename: Lv
authors.initials: L
authors.lastname: Yin
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality* / Q000628:therapy; D016022:Case-Control Studies; D049109:Cell Proliferation; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000494:pharmacology; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000628:therapy; D004947:Esophagus / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000097577:Homeobox Protein PITX2
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002945:Cisplatin; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2