Nano Let-7b sensitization of eliminating esophageal cancer stem-like cells is dependent on blockade of Wnt activation of symmetric division

Abstract

The poor therapy response and poor prognosis of esophageal cancer has made it one of the most malignant carcinoma, and the complicated multidisciplinary treatment failed to achieve a long-term disease-free survival. To diagnose esophageal cancer at an earlier stage, and to improve the effect of anticancer therapy would improve the therapeutic efficacy. After retrospective analysis of the cancer samples of patients who received esophagectomy, we found the relevance between ratio of either ALDH1 or CD133-positive cancer stem cells and 2-year recurrence. Higher ratios of cancer stem cells indicated later clinical stages, and Wnt signaling activation was more frequent in later esophageal carcinoma. Further in bench studies, we explored the suppressive roles and the mechanisms involved in Let-7 on self-renewal in ECA-109 and ECA-9706 esophageal cancer stem cells. Isolated cancer stem cells naturally divide symmetrically and are therapy resistant. Therapy of fluorouracil and docetaxel both enriched the stem cells, proving the resistant characteristics of cancer stem cells. Wnt activation stimulated more symmetric division of stem cells, resulting in self-renewal promotion, which could be blocked by Let-7 overexpression. Furthermore, enforced Let-7 sensitized the stem cells to chemotherapies in a Wnt pathway inhibition-dependent manner, contributing to Let-7 sensitization of chemotherapeutic response. Wnt activation weakened the suppressive Let-7b through the sponge functions of CCAT-1, forming the negative feedback loop of Let-7b/Wnt/CCAT1. These results identified the crucial participation of stem cells in esophageal cancer occurrence and progression as the potent indicator, and also indicate the potential powerful agent of Let-7 nano-particles in treatment of cancer.

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