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.
Exosomes from oxaliplatin‐resistant colorectal cancer (CRC) cells transferred ciRS‐122 to oxaliplatin‐sensitive cells, enhancing glycolysis and drug resistance by promoting PKM2 expression. Furthermore, ciRS‐122 targeting through exosome‐delivered small interfering (si)RNA in vivo enhanced the drug response, indicating a novel potential approach for the reversion of oxaliplatin resistance in CRC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cancer stem cells (CSCs) are an important cause of tumor recurrence and drug resistance. As a new type of cell death that relies on iron ions and is strictly regulated by intracellular and ...extracellular signals, the role of ferroptosis in tumor stem cells deserves extensive attention. Mass spectrum was applied to screen for ferroptosis-related proteins in gastric cancer (GC). Sphere-formation assay was used to estimate the stemness of gastric cancer stem cells (GCSCs). Exosomal lnc-ENDOG-1:1 (lncFERO) was isolated by ultracentrifugation. Ferroptosis was induced by erastin and was assessed by detecting lipid ROS, mitochondrial membrane potential, and cell death. Furthermore, a series of functional in vitro and in vivo experiments were conducted to evaluate the effects of lncFERO on regulating ferroptosis and chemosensitivity in GCSCs. Here, we showed that stearoyl-CoA-desaturase (SCD1) played a key role in regulating lipid metabolism and ferroptosis in GCSCs. Importantly, exosomal lncFERO (exo-lncFERO) derived from GC cells was demonstrated to promote SCD1 expression by directly interacting with SCD1 mRNA and recruiting heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which resulted in the dysregulation of PUFA levels and the suppression of ferroptosis in GCSCs. Moreover, we found that hnRNPA1 was also involved in lncFERO packing into exosomes in GC cells, and both in vitro and in vivo data suggested that chemotoxicity induced lncFERO secretion from GC cells by upregulating hnRNPA1 expression, leading to enhanced stemness and acquired chemo-resistance. All these data suggest that GC cells derived exo-lncFERO controls GCSC tumorigenic properties through suppressing ferroptosis, and targeting exo-lncFERO/hnRNPA1/SCD1 axis combined with chemotherapy could be a promising CSC-based strategy for the treatment of GC.
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.
HGF siRNA packed in exosomes can be transported into cancer cells, and down‐regulates HGF expression, and suppress proliferation and migration of both cancer cells and vascular cells.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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.
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.
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.
Fatty acid oxidation (FAO) plays a vital role in drug resistance in cancer cells. Carnitine palmitoyltransferase 1A (CPT1A), a key enzyme of FAO, is widely recognized as an emerging therapeutic ...target. Here, we confirmed that CPT1A was heterogeneously expressed in colon cancer cells, with a high expression in oxaliplatin‐resistant cells but low expression in oxaliplatin‐sensitive cells, and expression could be increased by oxaliplatin stimulation. In addition, we verified that CPT1A was more highly expressed in colon cancer tissues than in noncancerous tissues. Silencing CPT1A by siRNA or etomoxir, a specific small‐molecule inhibitor of CPT1A, could reverse the sensitivity of drug‐resistant colon cancer cells to oxaliplatin. Subsequently, the combination of oxaliplatin with CPT1A inhibition promoted apoptosis and inhibited proliferation. In addition, exosomes were generated with the iRGD peptide on the surface, which showed highly efficient targeting compared with control exosomes in vivo. Furthermore, we loaded and therapeutically applied iRGD‐modified exosomes with siCPT1A to specifically deliver siCPT1A into tumours to suppress FAO. As a consequence, iRGD‐modified exosomes showed the significant inhibition of CPT1A in tumour tissues and exhibited the ability to reverse oxaliplatin resistance and inhibit tumour growth by inhibiting FAO with high safety in vivo.
Fatty acid oxidation (FAO) plays a vital role in drug resistance in cancer cells. High expression of Carnitine palmitoyltransferase 1A (CPT1A), a key enzyme in FAO, was observed in colon cancer tissues. Here, we demonstrated that silencing of CPT1A by iRGD‐exosome‐siCPT1A efficiently suppressed FAO, inhibited tumorigenesis and reversed oxaliplatin resistance in colon cancer. Altogether, iRGD‐exosome‐siCPT1A mediated silencing of FAO may serve as an effective approach to treat oxaliplatin‐resistant patient with colon cancer and may propel the clinical application of iRGD‐engineered exosomes for siRNA delivery in cancer treatment.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background/Aims: Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Thus, methods for early diagnosis of CRC are ...urgently needed. We aimed to identify potential long non-coding RNAs (lncRNAs) in circulatory exosomes that may serve as biomarkers for the detection of early-stage CRC. Methods: Exosomes from the plasma of CRC patients (n = 50) and healthy individuals (n = 50) were isolated by ultracentrifugation, followed by extraction of total exosomal RNAs using TRIzol reagent. Microarray analysis was used for exosomal lncRNA profiling in the two groups, and real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to determine the expression level of lncRNAs in all patients and healthy subjects. Results: The expression of six lncRNAs (LNCV6_116109, LNCV6_98390, LNCV6_38772, LNCV_108266, LNCV6_84003, and LNCV6_98602) was found to be significantly up-regulated in CRC patients compared with that in healthy individuals by qRT-PCR. The receiver operating characteristic curve was used to verify their diagnostic accuracy. The values of the area under the curve for these lncRNAs were 0.770 (LNCV6_116109), 0.7500 (LNCV6_98390), 0.6500 (LNCV6_38772), 0.6900 (LNCV_108266), 0.7500 (LNCV6_84003), and 0.7200 (LNCV6_98602). Conclusion: Our study suggested that the expression of these six exosomal lncRNAs (LNCV6_116109, LNCV6_98390, LNCV6_38772, LNCV_108266, LNCV6_84003, and LNCV6_98602) was significantly up-regulated in the plasma of CRC patients, and that they may serve as potential non-invasive biomarkers for early diagnosis of CRC.
MicroRNAs (miRNAs) are involved in the progression of many cancers through largely unelucidated mechanisms. The results of our present study identified a gene cluster, miR‐221/222, that is ...constitutively upregulated in serum exosome samples of patients with colorectal carcinoma (CRC) with liver metastasis (LM); this upregulation predicts a poor overall survival rate. Using an in vitro cell coculture model, we demonstrated that CRC exosomes harboring miR‐221/222 activate liver hepatocyte growth factor (HGF) by suppressing SPINT1 expression. Importantly, miR‐221/222 plays a key role in forming a favorable premetastatic niche (PMN) that leads to the aggressive nature of CRC, which was further shown through in vivo studies. Overall, our results show that exosomal miR‐221/222 promotes CRC progression and may serve as a novel prognostic marker and therapeutic target for CRC with LM.
MiR‐221/222 is frequently upregulated in serum exosomal samples of patients with colorectal carcinoma (CRC) liver metastasis (LM). CRC exosome–delivered miR‐221/222 exerts a vital effect in promoting liver‐specific metastasis through remodeling the liver microenvironment. Tumor‐derived exosomal miR‐221/222‐3p can induce hepatic stromal cells to secrete HGF in the premetastatic niche (PMN).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Osteosarcoma is the most common primary sarcoma of bone, and it is a leading cause of cancer death among adolescents and young adults. However, the molecular mechanism underlying osteosarcoma ...carcinogenesis remains poorly understood. Recently, cyclin-dependent kinase 6 （CDK6） was identified as an important onco- gene. We found that CDK6 protein level, rather than CDK6 mRNA level, is much higher in osteosarcoma tissues than in normal adjacent tissues, which indicates a post-transcriptional mechanism involved in CDK6 regulation in osteosarcoma. MiRNAs are small non- coding RNAs that repress gene expression at the post- transcriptional level and have widely been shown to play important roles in many human cancers. In this study, we investigated the role of miR-29b as a novel regulator of CDK6 using bioinformatics methods. We demon- strated that CDK6 can be downregulated by miR-29b via binding to the 3＇-UTR region in osteosarcoma cells. Furthermore, we identified an inverse correlation between miR-29b and CDK6 protein levels in osteosar- coma tissues. Finally, we examined the function of miR- 29b-driven repression of CDK6 expression in osteosarcoma cells. The results revealed that miR-29b acts as a tumor suppressor of osteosarcoma by targeting CDK6 in the proliferation and migration processes. Taken together, our results highlight an important role for miR-29b in the regulation of CDK6 in osteosarcoma and may open new avenues for future osteosarcoma therapies.
ALL (Acute lymphoblastic leukemia) is the most common pediatric malignancy and T-ALL (T-cell acute lymphoblastic leukemia) comprises about 15% cases. Compared with B-ALL (B-cell acute lymphoblastic ...leukemia), the prognosis of T-ALL is poorer, the chemotherapy is easier to fail and the relapse rate is higher. Previous studies mainly focused in Notch1-related long non-coding RNAs (lncRNAs) in T-ALL. Here, we intend to investigate lncRNAs involved in T-ALL covering different subtypes. The lncRNA PPM1A-AS was screened out for its significant up-regulation in 10 T-ALL samples of different subtypes than healthy human thymus extracts. Besides, the PPM1A-AS expression levels in 3 T-ALL cell lines are markedly higher than that in CD45
+
T cells of healthy human. We further demonstrate that PPM1A-AS can promote cell proliferation and inhibit cell apoptosis
in vitro
and can influence T-ALL growth
in vivo
. Finally, we verified that PPM1A-AS can regulate core proteins, Notch4, STAT3 and Akt, of 3 important signaling pathways related to T-ALL. These results confirm that lncRNA PPM1A-AS can act as an oncogene in T-ALL and maybe a potential clinical target of patients resistant to current chemotherapy or relapsed cases.
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