Let-7 Expression Is a Significant Determinant of Response to Chemotherapy through the Regulation of IL-6/STAT3 Pathway in Esophageal Squamous Cell Carcinoma

Abstract

Purpose: Cisplatin-based chemotherapy is widely used for esophageal cancer, sometimes in combination with surgery/radiotherapy, but poor response to chemotherapy is not uncommon. The aim of this study was to examine whether miRNA expression is useful to predict the response to chemotherapy in patients with esophageal cancer.Experimental Design: Using pretreatment biopsy samples from 98 patients with esophageal cancer who received preoperative chemotherapy, we measured the expression level of several miRNAs whose expression was altered in cisplatin-resistant esophageal cancer cell lines compared with those parent cell lines and examined the relationship between the miRNA expression and response to chemotherapy. In vitro assays were conducted to clarify the mechanism of miRNA-induced changes in chemosensitivity.Results: The expression levels of 15 miRNAs were altered in cisplatin-resistant cells. Of these, low expression of let-7b and let-7c in before-treatment biopsies from 74 patients of the training set correlated significantly with poor response to chemotherapy, both clinically and histopathologically. Low expression of let-7c also correlated with poor prognosis (P ¼ 0.032). The relationship between let-7b and let-7c expression and response to chemotherapy was confirmed in the other 24 patients of the validation set. In in vitro assay, transfection of let-7c restored sensitivity to cisplatin and increased rate of apoptosis after exposure to cisplatin. Let-7c directly repressed cisplatin-activated interleukin (IL)-6/STAT3 prosurvival pathway.Conclusions: Let-7 expression in esophageal cancer can be potentially used to predict the response to cisplatin-based chemotherapy. Let-7 modulates the chemosensitivity to cisplatin through the regulation of IL-6/STAT3 pathway in esophageal cancer.

Upregulation of let‑7f‑5p promotes chemotherapeutic resistance in colorectal cancer by directly repressing several pro‑apoptotic proteins

“…Downregulation of let-7 was also associated with chemoresistance in breast cancer cells (39). In addition, Sugimura et al (38) reported that low expression of let-7b and let-7c was significantly associated with a poor response to chemotherapy in esophageal squamous cell carcinoma, and that transfection of let-7c restored sensitivity to cisplatin and increased the rate of apoptosis following exposure to cisplatin in vitro assays. Additionally, Tsang and Kwok (34) reported that induced expression of let-7a increased the resistance of human squamous carcinoma A431 cells to chemotherapeutic drugs, including interferon-γ, doxorubicin and paclitaxel.…”

“…Furthermore, emerging evidence has demonstrated that members of the let-7 family of miRNAs are downregulated in a number of types of human cancer, and that low let-7 expression has been correlated with resistance to chemotherapeutics (37,38). Downregulation of let-7 was also associated with chemoresistance in breast cancer cells (39).…”

microRNA-186 inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma by targeting SKP2

“…miRNAs, including miR-21, miR-31, miR-577, etc, act as oncogenes, [19][20][21] while others such as Let-7, miR-98, miR-100, miR-138, miR-143, miR-150, etc, function as tumor suppressors. [22][23][24][25][26][27] However, the role of miR-186 in ESCC progression remains uninvestigated.…”

Molecular interplay of pro-inflammatory transcription factors and non-coding RNAs in esophageal squamous cell carcinoma

“…Besides, an inverse correlation of miR-138 levels and NF-κB expression in ESCC patient samples provides further support for this regulation. Let-7, a tumor suppressor miRNA downregulated in multiple forms of cancer, including ESCC, 63 downregulates Ras and IL-6, well-known oncogenes which are upstream activators of the NF-κB pathway. 64 Other miRNAs may have pro-oncogenic effects through stimulation of NF-κB signaling.…”