Exosome‐delivered circRNA promotes glycolysis to induce chemoresistance through the miR‐122‐PKM2 axis in colorectal cancer

Abstract

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.

Circ_0030998 Promotes Tumor Proliferation and Angiogenesis by Sponging miR-567 to Regulate VEGFA in Colorectal Cancer

“…Till now, more than 100,000 human circRNAs have been discovered 23,24 , and many of them have been detected playing important roles in various physiological and pathological processes such as cell differentiation 25 , cell cycle progression 26 , cellular proliferation 27 , apoptosis of cancer cells 28 , immune tolerance 29 and so on. Several circRNAs have been validated effective in the progression of CRC 16,17,18 . In the present study, we analyzed the microarray data GSE138589, which compared differentially expressed circRNAs in six pairs of CRC tissues and matched neighboring normal tissues, and con rmed a new circRNA, Circ_0030998, was upregulated in CRC tissues.…”

“…The covalently closed loop structure of circRNAs resulted in the high stability, which helped them to be ideal biomarkers. Several circRNAs have been detected involved in the progression of colorectal cancer 16,17,18 . However, identi cation of more functional circRNAs may facilitate the molecular-guided diagnosis and treatment of colorectal cancer.…”

Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance

“…For instance, hsa_circRNA_103306/miR-370-3p has the potential to regulate drug metabolism, while has_circ_32883/miR-130b probably affects drug resistance via the PI3K/AKT pathway [142]. Hsa_circ_32883 and ciRS-122 (hsa_circ_0005963) are upregulated in chemoresistant CRC cells [142,143]. CiRS-122 can be delivered into chemosensitive cells via oxaliplatin-resistant cells-secreted exosomes.…”

“…CiRS-122 can be delivered into chemosensitive cells via oxaliplatin-resistant cells-secreted exosomes. Then, it promotes glycolysis and cell resistance to oxaliplatin by sponging miR-122 to upregulate the M2 isoform of pyruvate kinase (PKM2) level [143]. Circ_001680 is increased in CRC tissues.…”

Extracellular Vesicle-Based Nucleic Acid Delivery: Current Advances and Future Perspectives in Cancer Therapeutic Strategies

“…In gastric cancer cells, the long noncoding RNA HOXA transcript at the distal tip (HOTTIP) was able to promote resistance to cisplatin by regulating miR-218, which targets the HMGA1 gene, a tumor promoter in several cancers [ 143 ]. In colorectal cancer, hsa_circ_0005963 acted as a miR-122 sponge, causing overexpression of the PKM2 gene and consequently resistance to oxaliplatin [ 144 ]. One of the limitations associated with EV therapy concerns its production site.…”