S100A14: Novel Modulator of Terminal Differentiation in Esophageal Cancer

Abstract

Aberrant keratinocyte differentiation is a key mechanism in the initiation of cancer. Because activities regulating differentiation exhibit altered or reduced capacity in esophageal cancer cells, it is vital to pinpoint those genes that control epidermal proliferation and terminal differentiation to better understand esophageal carcinogenesis. S100A14 is a member of the S100 calcium-binding protein family and has been suggested to be involved in cell proliferation, apoptosis, and invasion. The present study used immunohistochemistry analysis of S100A14 in clinical specimens of esophageal squamous cell carcinoma (ESCC) to show that decreased S100A14 is strongly correlated with poor differentiation. Furthermore, both mRNA and protein expression of S100A14 was drastically increased upon 12-O-tetra-decanoylphorbol-13-acetate (TPA) and calcium-induced esophageal cancer cell differentiation. Overexpression of S100A14 resulted in a G 1 -phase cell cycle arrest and promoted calcium-inhibited cell growth. Conversely, decreasing S100A14 expression significantly promoted G 1 -S transition and prevented the morphologic changes associated with calcium-induced cell differentiation. Molecular investigation demonstrated that S100A14 altered the calcium-induced expression of late markers of differentiation, with the most prominent effect on involucrin (IVL) and filaggrin (FLG). Finally, it was determined that S100A14 is transcriptionally regulated by JunB and that S100A14 and JunB status significantly correlated in ESCC tissue. In summary, these data demonstrate that S100A14 is transcriptionally regulated by JunB and involved in ESCC cell differentiation.

Krüppel-like Factor 4 Promotes Esophageal Squamous Cell Carcinoma Differentiation by Up-regulating Keratin 13 Expression

“…Calcium is another commonly used differentiation inducer, and our previous study showed that calcium induced the expression of a series of differentiation-associated genes in esophageal cancer cells, inhibited cell growth, and induced G 1 /S phase arrest and cell apoptosis. Moreover, calcium treatment induced an apparent cell-stratified and dramatic change in cell-cell contact (28), the effect of which coincides with SB. To further confirm the increased expression of KLF4 and KRT13 during the differentiation induction, we treated esophageal cancer cell lines KYSE150 and KYSE450 with 2.4 mM calcium that had been corroborated effectively by our previous results.…”

“…KLF5 played an essential role in the differentiation and homeostasis of epithelial cells, smooth muscle cells and adipocytes by regulating the expression of KRT5, SM22␣, peroxisome proliferator-activated receptor ␥ and others (39,40). Our previous results showed that KLF4 could bind directly to the promoter of S100A14 and activate its transcription, which modulated the terminal differentiation in esophageal cancer (26,28). cDNA microarray analysis also revealed a group of KRT genes, especially those located in a specific region on chromosome 12 could be induced by KLF4 (10).…”

Downregulation of 425G>A variant of calcium-binding protein S100A14 associated with poor differentiation and prognosis in gastric cancer

“…We provide evidence of the role of S100A14 in GC, which demonstrated that differential expression of S100A14 was related to GC differentiation. The observations showed that decreased expression of S100A14 was strongly correlated with poor ESCC differentiation (Chen et al 2013) or colorectal cancer (Wang et al 2010). Although this apparent relationship between S100A14 and tissue differentiation was consistent, these types of "differentiation" are quite different in meaning and mechanism.…”

“…The role of S100A14 in tumor underlying mechanisms might be complicated. For example, molecular investigation in ESCC illustrated the mechanism of S100A14 affecting the calcium-induced expression of late markers of differentiation, with the most prominent effect on involucrin and filaggrin (Chen et al 2013). The molecular mechanism involved in S100A14 and differentiation in GC or colorectal cancer are still not clear, whereas, in other tumors, such as epithelial ovarian cancers (Cho et al 2014), hepatocellular carcinoma, and breast cancer, overexpressed S100A14 was not correlated with differentiation, but with proliferation, invasion, metastasis, and even poor prognosis.…”

Inhibitor of Differentiation/DNA Binding 1 (ID1) Inhibits Etoposide-induced Apoptosis in a c-Jun/c-Fos-dependent Manner

“…This study was approved by the Institutional Review Board of the Chinese Academy of Medical Sciences Cancer Institute and Hospital. A tissue microarray from 110 patients with ESCC was previously made in our lab (28).…”