MicroRNA-203 inhibits the progression of esophageal squamous cell carcinoma with restored epithelial tissue architecture in vivo

Abstract

MicroRNA (miR)-203 has been shown to induce squamous differentiation of epidermal stem cells through the suppression of p63. The aim of this study was to assess the tumor suppressor effect of miR-203 in esophageal squamous cell carcinoma (ESCC) with focus on the regulation of the cell fate decisions and organization of tumor tissue architecture in vivo. Our investigation establishing stable clones from ESCC cell lines with induced miR-203 expression resulted in significant growth inhibition in a mouse xenograft model. Small foci were observed in xenograft tumors with stratified squamous differentiation in conjunction with restored baso-apical polarity. The expression of the basement membrane protein laminine was localized at the center of the foci and the basal cell marker p75NTR was expressed in the innermost layer. The expression of ki67 and p63 was co-localized at the center layers, while involucrin was expressed in the outer layers. Flow cytometry revealed that the p75NTR-positive cells expressing p63 and Bmi1 were well maintained, while the expression of p63 was suppressed in the p75NTR-negative cells. Our cDNA microarray analysis demonstrated the upregulation of genes involved in regulating tissue architecture, such as BMP-4 and ZO-1 in the mir-203 transfectant. Investigation using surgically removed ESCC specimens revealed that the expression of miR-203 significantly correlated with a favorable prognosis. These results demonstrated that miR-203 regulated both basal and supra-basal cell components to induce differentiation with restored epithelial tissue architecture, leading to significant tumor growth inhibition in vivo. Those results suggest the use of miR-203 as a novel therapeutic and diagnostic target in patients with ESCC.

Abnormal cell proliferation in the p75NTR-positive basal cell compartment of the esophageal epithelium during squamous carcinogenesis

“…C), finding compatible with the previous report in advanced ESCC that the expression of p75NTR is restricted in the most front layer of the infiltrative margin in diffusely proliferating ESCC lesions . Although the molecular mechanism which regulate p75NTR expression has not yet been elucidated, a recent report showed that induction of microRNA 203 into esophageal cancer cell lines resulted in restored tumor tissue polarity in vivo with expression of basement membrane proteins and localization of p75NTR expression in the basal layer, suggesting that interaction between the basal cells and basement membrane may play a role in regulation of p75NTR expression.…”

MicroRNA-203 induces apoptosis by upregulating Puma expression in colon and lung cancer cells

“…The uncertainty of miR-203 function may be due to its targeted activity against numerous molecules involved in a variety of cellular functions. Some of its targets include p63, Akt2, BMI1, and LASP1 which are responsible for cellular proliferation, apoptosis, and chemoresistance (40)(41)(42)(43)(44)(45)(46). Even though our results are consistent with previously published data, we acknowledged that our study has some limitations.…”

Concise Review: Custodians of the Transcriptome: How MicroRNAs Guard Stemness in Squamous Epithelia

“…Referring to another epithelial example, miR‐203 was shown to induce differentiation of esophageal SCC cells to restore epithelial tissue architecture and inhibit tumor growth in murine xenograft models . Another laboratory demonstrated a similar inhibitory effect of miR‐203 in vitro on esophageal cancer stem‐like cells .…”