Malignant tumors, including colorectal cancer (CRC), usually rely on ATP generation through aerobic glycolysis for both rapid growth and chemotherapy resistance. The M2 isoform of pyruvate kinase (PKM2) has a key role in catalyzing glycolysis, and PKM2 expression varies even within a single tumor. In this study, we confirmed that expression of PKM2 is heterogeneous in CRC cells, namely high in oxaliplatin‐resistant cells but relatively low in sensitive cells, and found that chemoresistant cells had enhanced glycolysis and ATP production. In addition, we report a PKM2‐dependent mechanism through which chemosensitive cells may gradually transform into chemoresistant cells. The circular RNA hsa_circ_0005963 (termed ciRS‐122 in this study), which was determined to be a sponge for the PKM2‐targeting miR‐122, was positively correlated with chemoresistance. In vitro and in vivo studies showed that exosomes from oxaliplatin‐resistant cells delivered ciRS‐122 to sensitive cells, thereby promoting glycolysis and drug resistance through miR‐122 sponging and PKM2 upregulation. Moreover, si‐ciRS‐122 transported by exosomes could suppress glycolysis and reverse resistance to oxaliplatin by regulating the ciRS‐122–miR‐122–PKM2 pathway in vivo. Exosomes derived from chemoresistant CRC cells could transfer ciRS‐122 across cells and promote glycolysis to reduce drug susceptibility in chemosensitive cells. This intercellular signal delivery suggests a potential novel therapeutic target and establishes a foundation for future clinical applications in drug‐resistant CRC.

Hepatocellular carcinoma (HCC), the major form of liver cancer, has shown increasing incidence and poor prognosis. Adipose tissue is known to function in energy storage and metabolism regulation by the secretion of adipokines. Circular RNAs (circRNAs), a novel type of noncoding RNA, have recently been recognized as key factors in tumor development, but the role of exosome circRNAs derived from adipose tissues has not been defined yet. Here, adipose-secreted circRNAs were found to regulate deubiquitination in HCC, thus facilitating cell growth. It was observed that exosome circ-deubiquitination (circ-DB) is upregulated in HCC patients with higher body fat ratios. Moreover, in vitro and in vivo studies showed that exo-circ-DB promotes HCC growth and reduces DNA damage via the suppression of miR-34a and the activation of deubiquitination-related USP7. Finally, the results showed that the effects of adipose exosomes on HCC cells can be reversed by knockdown of circ-DB. These results indicate that exosome circRNAs secreted from adipocytes promote tumor growth and reduce DNA damage by suppressing miR-34a and activating the USP7/Cyclin A2 signaling pathway.

Cancer‐related cachexia is a metabolic syndrome characterized by a wasting disorder of adipose and skeletal muscle and is accompanied by body weight loss and systemic inflammation. The treatment options for cancer cachexia are limited, and the molecular mechanism remains poorly understood. Circular RNAs (circRNAs) are a novel family of endogenous noncoding RNAs that have been proposed to regulate gene expression in mammals. Exosomes are small vesicles derived from cells, and recent studies have shown that circRNAs are stable in exosomes. However, little is known about the biological role of circRNAs in exosomes. In our study, we showed that circRNAs in plasma exosomes have specific expression features in gastric cancer (GC), and ciRS‐133 is linked with the browning of white adipose tissue (WAT) in GC patients. Exosomes derived from GC cells deliver ciRS‐133 into preadipocytes, promoting the differentiation of preadipocytes into brown‐like cells by activating PRDM16 and suppressing miR‐133. Moreover, knockdown of ciRS‐133 reduced cancer cachexia in tumor‐implanted mice, decreasing oxygen consumption and heat production. Thus, exosome‐delivered circRNAs are involved in WAT browning and play a key role in cancer‐associated cachexia.

The major environmental determinants of honeybee caste development come from larval nutrients: royal jelly stimulates the differentiation of larvae into queens, whereas beebread leads to worker bee fate. However, these determinants are not fully characterized. Here we report that plant RNAs, particularly miRNAs, which are more enriched in beebread than in royal jelly, delay development and decrease body and ovary size in honeybees, thereby preventing larval differentiation into queens and inducing development into worker bees. Mechanistic studies reveal that amTOR, a stimulatory gene in caste differentiation, is the direct target of miR162a. Interestingly, the same effect also exists in non-social Drosophila. When such plant RNAs and miRNAs are fed to Drosophila larvae, they cause extended developmental times and reductions in body weight and length, ovary size and fecundity. This study identifies an uncharacterized function of plant miRNAs that fine-tunes honeybee caste development, offering hints for understanding cross-kingdom interaction and co-evolution.

Hypoxia is one of the important properties of solid tumor. However, oxygen supply within tumors is generally heterogeneous according to the distance from the nearest blood vessel. The discrepancy of metastatic potential exists between hypoxic cancer cells and relatively normoxic cancer cells. But the molecular mechanism remains poorly understood. Methods: Differential expression of circRNAs in plasma exosomes of CRC patients and normal subjects was performed by screening. Exosomes were isolated by ultra-centrifugation and RNA expressions were determined by RT-qPCR. The migratory capacity of cells was performed by high intension imaging, wound healing assay and transwell chamber migration assay. Results: Circ-133 is enriched in the plasma exosomes of CRC patients and increased with the disease progression. Exosomal circ-133 derived from hypoxic cells delivered into normoxic cells and promoted cancer metastasis by acting on miR-133a/GEF-H1/RhoA axis. Meanwhile, animal experiments revealed that knockdown of circ-133 can inhibit tumor metastasis. Circ-133 is expected to be a new biomarker for monitoring tumor progression and might be a novel therapeutic target. Conclusions: Hypoxia-derived exosomal circ-133 transported into normaxic cancer cells and promoted cell migration via miR-133a/GEF-H1/RhoA axis. This study reveals a potential mechanism for that the intra-tumor heterogeneity of oxygen promote cancer progression.

Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNA. Hepatocyte growth factor (HGF) is known to promote the growth of both cancer cells and vascular cells, and the HGF‐cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically downregulates HGF expression. A cell co‐culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNA.

Oxaliplatin resistance is a challenge in the treatment of colorectal cancer (CRC) patients. Regulatory T cells (Tregs) are well known for their immunosuppressive roles, and targeting Tregs is an effective way to improve chemosensitivity. Exosome-delivered microRNA (miRNA) might be used as a potential biomarker for predicting chemosensitivity. However, the relationship between Tregs and exosomal miRNAs remains largely unknown. TaqMan low-density array was performed to screen the differentially expressed serum miRNAs from pooled serum of patients who had FOLFOX treatment. Differential expression was validated using qRT-PCR in individual samples. Exosomes were isolated by sequential differential centrifugation, and they were verified by transmission electron microscopy. The RNA and protein levels were determined by quantitative realtime PCR and western blotting. A mouse xenograft model was adopted to evaluate the correlation between exosome-derived miR-208b and Tregs in vivo. We demonstrated that circulating miR-208b is a non-invasive marker for predicting FOLFOX sensitivity in CRC. miR-208b in colon cancer was secreted by tumor cells in the pattern of exosomes, and oxaliplatin-resistant cells showed the most obvious phenomenon of miR-208b increase. Colon cancer cell-secreted miR-208b was sufficiently delivered into recipient T cells to promote Treg expansion by targeting programmed cell death factor 4 (PDCD4). Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-208b resulted in tumor growth and oxaliplatin resistance. Our results demonstrate that tumor-secreted miR-208b promotes Treg expansion by targeting PDCD4, and it may be related to a decrease of oxaliplatin-based chemosensitivity in CRC. These findings highlight a potential role of exosomal miR-208b as a predictive biomarker for oxaliplatin-based therapy response, and they provide a novel target for immunotherapy.

Lung cancer remains the leading cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer cases. Recently, microRNAs (miRNAs) have been consistently demonstrated to be involved in NSCLC and to act as either tumor oncogenes or tumor suppressors. In this study, we identified a specific binding site for miR-218-5p in the 3′-untranslated region of the epidermal growth factor receptor (EGFR). We further experimentally validated miR-218-5p as a direct regulator of EGFR. We also identified an inverse correlation between miR-218-5p and EGFR protein levels in NSCLC tissue samples. Moreover, we demonstrated that miR-218-5p plays a critical role in suppressing the proliferation and migration of lung cancer cells probably by binding to EGFR. Finally, we examined the function of miR-218-5p in vivo and revealed that miR-218-5p exerts an anti-tumor effect by negatively regulating EGFR in a xenograft mouse model. Taken together, the results of this study highlight an important role for miR-218-5p in the regulation of EGFR in NSCLC and may open new avenues for future lung cancer therapies.