HPV16 E6/E7 promote the translocation and glucose uptake of GLUT1 by PI3K/AKT pathway via relieving miR-451 inhibitory effect on CAB39 in lung cancer cells

Abstract

Background: HPV16 E6/E7 proteins are the main oncogenes and only long-term persistent infection causes lung cancer. Our previous studies have shown that HPV16 E6/E7 protein up-regulates the expression of GLUT1 in lung cancer cells. However, whether E6 and E7 protein can promote the glucose uptake of GLUT1 and its molecular mechanism are unclear. Methods: The regulatory relationships of E6 or E7, miR-451, CAB39, PI3K/AKT, and GLUT1 were detected by double directional genetic manipulations in lung cancer cell lines. Immunofluorescence and flow cytometry were used to detect the effect of CAB39 on promoting the translocation to the plasma membrane of GLUT1. Flow cytometry and confocal microscopy were performed to detect the glucose uptake levels of GLUT1. Results: The overexpression both E6 and E7 proteins significantly down-regulated the expression level of miR-451, and the loss of miR-451 further up-regulated the expression of its target gene CAB39 at both protein and mRNA levels. Subsequently, CAB39 up-regulated the expression of GLUT1 at both protein and mRNA levels. Our results demonstrated that HPV16 E6/E7 up-regulated the expression and activation of GLUT1 through the HPV–miR-451–CAB39–GLUT1 axis. More interestingly, we found that CAB39 prompted GLUT1 translocation to the plasma membrane and glucose uptake, and this promotion depended on the PI3K/AKT pathway. Conclusion: Our findings provide new evidence to support the critical roles of miR-451 and CAB39 in the pathogenesis of HPV-related lung cancer.

CAB39 mediates epithelial-mesenchymal transition via activation of NF-κB signaling to facilitate bladder cancer invasion and metastasis

“…reported in a study of gastric cancer, that suppression of cancer progression and oncogenic autophagy was achieved through reduction of CAB39, an upstream regulator of the AMPK/mTOR signaling pathway [31]. Furthermore, miRNA-451 targeting CAB39 suppressed proliferation and invasion of glioblastoma and lung cancer cells via mTOR/HIF-1a/VEGF and PIK3/AKT signaling pathways, respectively [25,32]. Finally, a link between NF-kB activation and transcriptional regulation of EMT-TFs has been indicated in certain human cancers [35][36][37][38].…”

“…From analysis of TCGA database, Ruhl et al noted increased CAB39 expression at the protein level in a signi cant portion of colon cancer patients associated with poorer overall survival [23]. Additionally, studies on microRNAs targeting CAB39 in gastric cancer, lung cancer, colorectal cancer, and glioma also suggest that CAB39 upregulation has stimulatory effect on cell proliferation, invasion, and oncogenic autophagy [25,[29][30][31]. Since CAB39 is evolutionarily conserved and ubiquitously expressed in a variety of human tissues, its oncogenic function is likely to be fundamental in most cell types and the association with tumor invasion and metastasis observed in BC can also occur in other types of cancers [32].…”

“…Since previous studies have revealed enhanced CAB39 expression in many types of cancers including colorectal cancer, gastric cancer, and hepatocellular cancer promoting cell proliferation and metastasis, the oncogene has become a favorable target for the treatment of these types of cancers. [23,25,[29][30][31][32]. Ruhl et al Found that in response to g-radiation, a speci c miRNA-451a could be rapidly upregulated to target and degrade CAB39 [23].…”

“…Godlewski et al reported that miR-451 can modulate the adaptation to metabolic stress in glioma through regulating CAB39 [22]. In addition, miR-451 has also been found to target and regulate CAB39 both at mRNA and protein levels in colorectal cancer, pancreatic cancer, and lung cancer [23][24][25]. Although emerging evidence regarding the role of CAB39 has been demonstrated in some cancers, its role in the development and progression of BC remains elusive.…”

ITGB1-DT/ARNTL2 axis may be a novel biomarker in lung adenocarcinoma: a bioinformatics analysis and experimental validation

“…It is well known that cancer cells consume more glucose for energy through the “Warburg effect” [ 51 ]. So, when SLC2A1 is abnormally activated in the plasma membrane of tumor cells, it can transport large amounts of glucose from the extracellular to the mitochondria, thus providing energy to the cancer cells [ 52 ]. According to previous research, SLC2A1 appears to serve as an oncogene in a variety of malignancies, including lung cancer [ 31 , 53 , 54 ], pancreatic cancer [ 28 ], oral cancer [ 55 ], and so on.…”