Background: 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. 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). Methods: CAFs 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. Results: FOXA1 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. Conclusion: The present study identifies miR-93-5p as a specific exosomal cargo that rescues CRC cells against radiation-induced apoptosis.
Radiotherapeutic resistance is a major obstacle for the effective treatment of colorectal cancer (CRC). MicroRNAs (miRNAs) play a critical role in chemoresistance and radioresistance. Here, we aimed to investigate whether miR-590-3p participates in the radioresistance of CRC. High expression of miR-590-3p and low expression of CLCA4 were found in both CRC tissues and cell lines. CLCA4 was indicated to be a target gene of miR-590-3p. CAF-derived exosomes were extracted and co-cultured with CRC cells, which were then exposed to radiation. CRC cells were transfected with plasmids and injected into nude mice to detect the
in vivo
effect of CAF-derived exosomes. Treatment with CAF-derived exosomes decreased the sensitivity of CRC cells to radiation. CAF-derived exosomes overexpressing miR-590-3p increased cell survival and the ratio of p-PI3K/PI3K and p-AKT/AKT while lowering the expressions of cleaved-PARP, cleaved-caspase 3, and γH2AX in cells. Furthermore,
in vivo
experimental results confirmed that CAF-derived exosomal miR-590-3p stimulated tumor growth in mice following radiotherapy. Our results demonstrate that miR-590-3p delivery via exosomes derived from CAFs enhances radioresistance in CRC through the positive regulation of the CLCA4-dependent PI3K/Akt signaling pathway.
Zeolitic imidazolate frameworks (ZIFs) are very useful as high-capacity iodine (I2) adsorbents. The adsorption performance is usually probed by measuring a statistical average property over an entire sample consisting of a large number of ZIF particles, leaving the interparticle heterogeneity information among individuals. Here we report a dark-field microscopy (DFM) method to visualize gaseous I2 adsorption on single ZIF-90 particles in situ and in real time. The adsorption of I2 is found to alter the scattering spectrum of ZIF-90 particles, inducing a distinct color change from bluewhite to yellow. According to correlating the adsorption amount of gaseous I2 with the change of B value from DFM images, we quantitatively image the adsorption process and estimate the related kinetic parameters at the single particle level. Single particle measurements clarify the large particle-to-particle heterogeneity in adsorption reactivity and significant adsorption activity improvement of ZIF-90 after introduction of linker defects, which provides a microscopic understanding of the structure-activity relationship. We further demonstrate the capacity of this strategy for studying gaseous I2 adsorption on single ZIF-91 particle as a derivative of ZIF-90 to illustrate the generality.
It has been reported that long non-coding RNA HOXA distal transcript antisense RNA (lncRNA HOTTIP) functions as a tumor promoter in colorectal cancer (CRC). Hence, we paid attention to exploring whether exosomes could carry lncRNA HOTTIP to affect the mitomycin resistance in CRC and to identify the underlying mechanisms. High expression of HOTTIP was detected in mitomycin-resistant CRC cells. Inhibition of HOTTIP reduced the mitomycin resistance. In the co-culture system of mitomycin-resistant cells or their derived exosomes with CRC cells, the HOTTIP was found to be transferred into the parental cells via extracellular vesicles (EVs) secreted from mitomycin-resistant cells and to contribute to the mitomycin resistance. Based on the bioinformatics databases, possible interaction network of HOTTIP, microRNA-214 (miR-214) and Karyopherin subunit alpha 3 (KPNA3) in CRC was predicted, which was further analyzed by dual-luciferase reporter, RNA binding protein immunoprecipitation and RNA pull-down assays. As HOTTIP down-regulated miR-214 to elevate the KPNA3 expression, HOTTIP enhanced the mitomycin resistance through impairing miR-214-dependent inhibition of KPNA3. Finally, HOTTIP was suggested as an independent factor predicting mitomycin response in patients with CRC. Those data together confirmed the promotive effects of EV-carried HOTTIP on the mitomycin resistance, while targeting HOTTIP might be a promising strategy overcoming drug resistance in CRC.
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