Mir‐488 alleviates chemoresistance and glycolysis of colorectal cancer by targeting PFKFB3

Abstract

Background Considering the boosting effect of glycolysis on tumor chemoresistance, this investigation aimed at exploring whether miR‐488/PFKFB3 axis might reduce drug resistance of colorectal cancer (CRC) by affecting glycolysis, proliferation, migration, and invasion of CRC cells. Method Totally, 288 CRC patients were divided into metastasis/recurrence group (n = 107) and non‐metastasis/recurrence group (n = 181) according to their prognosis about 1 year after the chemotherapy, and their 3‐year overall survival was also tracked. Besides, miR‐488 expression was determined in peripheral blood of CRC patients and also in CRC cell lines (ie, W620, HT‐29, Lovo, and HCT116). The targeted relationship between miR‐488 and PFKFB3 was predicted by Targetscan software and confirmed by dual‐luciferase reporter gene assay. Moreover, glycolysis and drug tolerance of CRC cells lines were assessed. Results MiR‐488 expression was significantly decreased in metastatic/recurrent CRC patients than those without metastasis/recurrence (P < .05), and lowly expressed miR‐488 was suggestive of unfavorable 3‐year survival, large tumor size, poor differentiation, in‐depth infiltration, and advanced Duke stage of CRC patients (P < .05). Besides, CRC cell lines transfected by miR‐488 mimic demonstrated decreases in glucose uptake and lactate secretion, increases in oxaliplatin/5‐Fu‐sensistivity, as well as diminished capability of proliferating, invading, and migratory (P < .05), which were reversible by extra transfection of pcDNA3.1‐PFKFB3 (ie, miR‐488 mimic + pcDNA3.1‐PFKFB3 group). Finally, the mRNA level of PFKFB3 was down‐regulated by miR‐488 mimic in CRC cell lines after being targeted by it (P < .05). Conclusion The miR‐488/PFKFB3 axis might clinically refine chemotherapeutic efficacy of CRC, given its modifying glycolysis and metastasis of CRC cells.

The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer

“…Antiangiogenic therapies combined with the inhibition of PFKFB3 not only recover the normal vascular barrier function and blood perfusion but also result in metabolic changes in endothelial cells or vascular leakage, further impairing the delivery of chemotherapeutic drugs (85,95). MiR-488 not only inhibits the proliferation and glycolysis of prostate cancer (96) but also inhibits oxaliplatin/5-FU resistance and glycolysis of colorectal cancer by targeting PFKFB3 (97). Liposomes coloaded with PFKFB3 shRNA plasmid significantly upregulate the cytotoxicity of docetaxel in non-small cell lung cancer (98).…”

Role of microRNAs in glycolysis in gynecological tumors (Review)

“…In other types of cancer, such as colorectal cancer, miR-488 directly targets PFKFB3, and PFKFB3 mRNA levels are inhibited by miR-488. This results in decreased glucose uptake and lactate secretion, increased sensitivity to chemotherapy drugs, and decreased proliferation, invasion, and migration (95,96). miR-3666 and miR-26b also reduce the rate of glycolysis through inhibiting the activity of PFKFB3; thus, contributing to tumor inhibition (97,98).…”

Emerging role of non-coding RNAs in glucose metabolic reprogramming and chemoresistance in colorectal cancer

“…MiR-149-3p has been found to promote 5-Fluorouracil (5-FU)-induced CRC cells apoptosis and inhibit the glucose metabolism by targeting PDK2 ( 24 ). MiR-488 is obviously decreased in metastatic/recurrent CRC, which can also refine the chemoresistance and glycolysis of CRC by targeting a key enzyme involved in glucose metabolism, namely, phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) ( 25 ). The study by Park GB et al.…”