Abstract
BackgroundCancer-associated fibroblasts (CAFs) have been intensively studied in recent studies with aims of finding more concrete evidence on their mechanism of involvement in tumor progression, which is currently unknown. CAFs can secrete exosomes which are loaded with proteins, lipids and RNAs, all of which affect tumor microenvironment. The present study identified microRNA-93-5p (miR-93-5p) as a novel exosomal cargo responsible for the pro-tumorigenic effects of CAFs on colorectal cancer (CRC).MethodsCAFs and normal fibroblasts (NFs) were isolated from cancerous tissues and matched with paracancerous tissues that had been surgically resected from CRC patients. The interaction among miR-93-5p, forkhead box A1 (FOXA1) and TGFB3 was identified through ChIP and dual luciferase reporter assays. The proliferation and apoptosis of SW480 cells co-cultured with CAFs-derived exosomes under irradiation were evaluated by CCK-8, colony formation, and flow cytometric assays. Tumorigenesis of SW480 cells in nude mice was assessed under the irradiation.ResultsFOXA1 was found to be associated with reduced radioresistance in CRC cells and was verified as a target of miR-93-5p. CAFs-derived exosomes contained higher miR-93-5p than those from NFs, which augmented SW480 cell proliferation and rescued them from radiation-induced apoptosis. miR-93-5p was identified as a mediator of the exosomal effects of CAFs on SW480 cells, possibly through downregulating FOXA1 and upregulating TGFB3. FOXA1 could bind to the promoter of TGFB3, thereby inhibiting nuclear accumulation of TGFB3. Also, CAFs-derived exosomes containing miR-93-5p increased the tumor growth of SW480 cells in irradiated nude mice.ConclusionThe present study identifies miR-93-5p as a specific exosomal cargo that rescues CRC cells against radiation-induced apoptosis.
Highlights
Cancer-associated fibroblasts (CAFs) have been intensively studied in recent studies with aims of finding more concrete evidence on their mechanism of involvement in tumor progression, which is currently unknown
colorectal cancer (CRC) cells often develop the resistance to radiotherapy, which remains an intractable problem in therapeutic effect and represents a major obstacle to reduce the death of CRC cells [4]
forkhead box A1 (FOXA1) is downregulated in CRC and inhibits chemoresistance of CRC cells Differential analysis was conducted for radiosensitive and radio-resistant CRC-related microarray data GSE3493, which identified 18 genes with significant difference in expression in radioresistant samples relative to radiosensitive samples (Fig. 1a)
Summary
Cancer-associated fibroblasts (CAFs) have been intensively studied in recent studies with aims of finding more concrete evidence on their mechanism of involvement in tumor progression, which is currently unknown. The present study identified microRNA-93-5p (miR-93-5p) as a novel exosomal cargo responsible for the pro-tumorigenic effects of CAFs on colorectal cancer (CRC). Colorectal cancer (CRC) is the third most common cancer worldwide, with 1–2 million new cases diagnosed annually and the fourth leading cause of cancer-related death, with 700,000 deaths reported every year [1]. CRC cells often develop the resistance to radiotherapy, which remains an intractable problem in therapeutic effect and represents a major obstacle to reduce the death of CRC cells [4]. It is reported that cancer-associated fibroblasts (CAFs), recruited from local tissue-resident fibroblasts or pericryptal fibroblasts and distant fibroblast precursors, is involved in therapeutic resistance in CRC cells [5]. Our research interests arouse considering the possible mechanism of CAFs in CRC
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