CD24 and CK4 are upregulated by SIM2, and are predictive biomarkers for chemoradiotherapy and surgery in esophageal cancer

Int J Oncol. 2020 Mar;56(3):835-847. doi: 10.3892/ijo.2020.4963. Epub 2020 Jan 17.


Definitive chemoradiotherapy (CRT) is a less invasive therapy compared with surgery for some types of cancer; however, the 5‑year survival rate of patients with stages II‑III esophageal squamous cell carcinoma (ESCC) is only 37%. Therefore, prediction of CRT responders is necessary. Unfortunately, no definitive biomarker exists that is useful to predict survival outcome following CRT. From our previous microarray study, CD24 and keratin 4 (KRT4), which encodes cytokeratin 4 (CK4), were overexpressed in the favorable prognostic epithelial subtype with SIM bHLH transcription factor 2 (SIM2) expression. This study investigated the association between their mRNA and protein expression levels, and clinicopathological characteristics, and also investigated the functions of CD24 in SIM2‑mediated tumor differentiation and CRT sensitivity. High CD24 and KRT4 mRNA expression was associated with a favorable prognosis following CRT. Multivariate analyses revealed that high CD24 and CK4 protein expression, as determined by immunohistochemistry, and differentiated type were independent factors for predicting a favorable prognosis in response to CRT. Notably, in cases with low CD24 or CK4, surgery was suggested to be a good therapeutic modality compared with CRT. CD24 and KRT4 were expressed preferentially in differentiated layers of the normal esophageal mucosa, and their mRNA expression in 3D cultured ESCC cells was induced by SIM2 transfection, thus suggesting that CD24 and KRT4 were downstream differentiation markers of SIM2. Furthermore, CD24 small interfering RNA increased the mRNA expression levels of superoxide dismutase 2 and enhanced H2O2 resistance, thus indicating the involvement of CD24 in the radiosensitivity of patients with ESCC; however, it had no effect on cisplatin sensitivity. In conclusion, the two markers CD24 and CK4 may be considered predictive biomarkers for definitive CRT.

Keywords: esophageal squamous cell carcinoma; SIM bHLH transcription factor 2; CD24; keratin 4; chemoradiotherapy.

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • CD24 Antigen / genetics*
  • CD24 Antigen / metabolism
  • Carcinoma, Small Cell / genetics
  • Carcinoma, Small Cell / metabolism
  • Carcinoma, Small Cell / pathology
  • Carcinoma, Small Cell / therapy*
  • Cell Line, Tumor
  • Chemoradiotherapy
  • Digestive System Surgical Procedures
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology
  • Esophageal Neoplasms / therapy*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Keratin-4 / genetics*
  • Keratin-4 / metabolism
  • Male
  • Neoplasm Staging
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • Survival Analysis
  • Survival Rate
  • Treatment Outcome
  • Up-Regulation*


  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • CD24 Antigen
  • CD24 protein, human
  • Keratin-4
  • SIM2 protein, human