ADIRF expression reversely correlates with stage progression and involves keratinocyte differentiation in esophageal squamous cell carcinoma

Background: Aberrant differentiation in esophageal mucosa was crucial for the carcinogenesis and development of esophageal squamous cell carcinoma (ESCC). However, few evidences elucidated the regulatory molecule during ESCC differentiation. We aimed to interpret the correlation between ADIRF expression and the tumor progression and reveal its molecular function in ESCC. Methods: : The ADIRF expression in ESCC was assessed in RNA-seq (RNA sequencing) data from a TCGA (The Cancer Genome Atlas) cohort and immunohistochemically examined in a tissue chip. The correlations with clinical data were assessed in 30 surgical specimens from our center. The regulating effects on cellular function were assessed in the established ADIRF overexpressed and suppressed ESCC cells. The molecular functions of ADIRF were inferenced according to the investigation of the correlated genes. Results: : Both in the mRNA level and in the protein level, expression of ADIRF was decreased in cancerous mucosa than normal tissues, and significantly downregulated in the advanced ESCCs than those in the early stage. ADIRF expression in ESCCs was reversely correlated with the progressing of AJCC stage ( r =-0.41) and tumor stage ( r =-0.56). The high expression of ADIRF was efficient to distinguish patients with superficial invasion from those with deeper invasion (AUC=0.805, P<0.001). In vitro, ADIRF showed a suppression role and obviously inhibited the proliferation, migration and division of ESCC cells. According to functional analysis of the coexpressed genes, the ADIRF was putatively associated with the keratinocyte differentiation. Among the keratinocyte differentiation associated genes, SPRR1A, SPRR1B, PKP3, SPRR2D, and FLG were detected to independently correlate with the ESCC prognosis. Thereinto, SPRR1A was with the minimum hazard ratio (HR=0.11, 95%CI: 0.02-0.62) and significantly downregulated in the advanced ESCCs. Conclusions: : This study uncovers that ADIRF was reversely correlated with ESCC progression and suppressed malignancy of tumor cells. Moreover, ADIRF was speculated to regulate esophageal keratinocyte differentiation. Hence, ADIRF might be a suppressive factor and with keratinocyte differentiation regulating effect in ESCC.