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

Abstract

Abstract. Colorectal cancer (CRC) is one of the most frequently occurring primary malignant tumors worldwide. Chemotherapeutic resistance is a major clinical problem in the treatment of CRC. Therefore, it is of great importance to investigate novel biomarkers that may predict chemoresistance and facilitate the development of individualized treatment for patients with CRC. The present study reported that let-7f-5p expression was elevated in chemotherapy-resistant CRC tissues compared with chemotherapy-sensitive tissues. Furthermore, upregulating let-7f-5p increased the expression levels of the anti-apoptotic proteins, B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), and decreased the activity of caspase-3 and caspase-9 in CRC cells. By contrast, downregulating let-7f-5p yielded the opposite effect. Notably, the results indicated that let-7f-5p promoted chemotherapeutic resistance by directly repressing the expression of several pro-apoptotic proteins, including tumor protein p53, tumor protein p53-inducible nuclear protein 1, tumor protein p53-inducible nuclear protein 2 and caspase-3. Therefore, a novel mechanism by which let-7f-5p enhances the resistance of CRC cells to chemotherapeutics has been revealed, indicating that silencing let-7f-5p may become an effective therapeutic strategy against CRC. IntroductionColorectal cancer (CRC) is one of the most prevalent causes of cancer-associated mortality worldwide (1,2). Clinically, 5-fluorouracil (5-FU)-based chemotherapy serves as the initial first-line chemotherapeutic drug of choice in patients with CRC; however, the response rates to 5-FU are ~15% in patients with advanced CRC (3). Although novel therapeutic approaches, including combination chemotherapy of 5-FU and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), have presented promising potential, the majority of the patients continue to exhibit inadequate responses (4,5). The failure of chemotherapy in CRC patients is primarily attributed to therapeutic resistance following a long period of treatment (6). These observations emphasize that chemotherapeutic resistance is a major obstacle in the treatment of CRC, and that the molecular mechanisms underlying this issue remain unclear.Chemotherapeutic resistance poses a major challenge in cancer chemotherapy. Chemoresistance of tumor cells develops primarily due to acquired resistance de novo, following an initially sensitive response, and/or in combination with pre-established cell-intrinsic mechanisms (7). A number of well-established mechanisms are reported to be involved in cancer drug resistance, including failure of the drug to reach or enter the target cell, formation of efflux pumps on the surface of tumor cells, increased expression of anti-apoptotic proteins, induction of drug-detoxifying mechanisms and upregulation of DNA repair enzymes (8,9). However, there is an absence of integral understanding of acquired drug resistance in the context of CRC. Such insight may be crucial for the

Contributions of Gene Modules Regulated by Essential Noncoding RNA in Colon Adenocarcinoma Progression

“…Also, downregulated miR-106b-5p was negatively associated with lymph node metastasis [49]. Upregulation of let-7f-5p [50] and XIST [51] enhances chemotherapeutic resistance in CRC.…”

Circulating let-7f-5p improve risk prediction of prostate cancer in patients with benign prostatic hyperplasia

“…The role of let-7f-5p have investigated in other diseases. The expression level of let-7f-5p was upregulated in colon cancer [25,26], thyroid cancer cells [27], typical and atypical carcinoid tumors [28]. However, downregulation of let-7f-5p was observed in amyotrophic lateral sclerosis [29].…”

“…However, downregulation of let-7f-5p was observed in amyotrophic lateral sclerosis [29]. Besides, a recent study found that let-7f-5p promoted the resistance of colorectal cancer cells and silence of let-7f-5p may provide a novel therapeutic strategy for colorectal cancer [26]. The role of let-7f-5p acted as biomarker was also explored.…”

Expression profiling of microRNAs and isomiRs in conventional central chondrosarcoma

“…7f-5p miRNA has been found to inhibit apoptosis and to promote chemotherapeutic resistance in some tumors 30,31 .…”