Aberrant microRNA (miRNA) expression in cancer affects the transcription of target genes, and profoundly influences cancer‑associated signaling pathways. Radiation resistance is a major problem ...encountered in the treatment of cancer. The present study aimed to investigate the role of miRNA (miR)‑21 in the development of radiation resistance in non‑small cell lung cancer cells. A radiation‑resistant cell line was generated from A549 cells. Significant upregulation of miR‑21 was detected in the radioresistant cancer cells, as compared with the radiosensitive cells, and overexpression of miR‑21 rendered A549 parental cells resistant to radiation. In addition, glycolysis was increased in the radioresistant cells, as compared with the sensitive cells. Furthermore, hypoxia‑inducible factor‑1α (HIF1α) was upregulated by miR‑21 in radioresistant cells, resulting in promotion of the key enzymes of glycolysis. Inhibition of HIF1α by small interfering RNA suppressed glycolysis and resensitized the cancer cells to radiation, whereas the recovery of HIF1α in miR‑21‑inhibited radioresistant cells resulted in recovery of radioresistance. In conclusion, the present study suggested that miR‑21 may modulate radioresistance through the upregulation of HIF1α. These results may provide a novel perspective on miRNA for the development of anti-radioresistance drugs.
Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature that is characterized by vascular obstruction and progressive right ventricular failure. One hallmark of clinical PAH ...is its very poor survival, with PAH mortality rates approximating those of many malignancies. The discovery that the fawn-hooded rat strain (FHR) spontaneously develops PAH has allowed for major insights into the pathophysiology of PAH. These findings have revealed that cancer and PAH not only share a similarly poor prognosis but also demonstrate similar resistance to apoptosis and activation of cell proliferation as a major pathophysiologic mechanism. One of the causes for the resistance to apoptosis and increased proliferation of pulmonary vascular smooth muscle cells in PAH is a cancer-like metabolic shift towards a glycolytic metabolism (Warburg effect) and down-regulation of mitochondrial glucose oxidation. This book chapter will review the role of such a metabolic shift in the pathophysiology of PAH and also highlight emerging anti-proliferative PAH therapies that correct the metabolic dysregulation in PAH.
Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 (PD-1) signaling pathway have dramatically improved the clinical outcomes of oncological patients having advanced ...non-small cell lung carcinoma (NSCLC). The immunohistochemical analysis of programmed death-ligand 1 (PD-L1) expression remains the most widely used and clinically validated bio-marker predicting efficacy of ICI in NSCLC patients, but it represents in isolation an imperfect tool. The PD-1 axis is intricately coupled with numerous cellular and molecular factors within the tumor microenvironment (TME) of NSCLC. Cellular factors implicated in the regulation process of PD-L1 expression in NSCLC are related to the activity of tumor infiltrating lymphocytes and cancer associated fibroblasts. Intrinsic molecular factors which affect the level of PD-L1 expression are associated with the presence of oncogenic driver mutations in the Kirsten rat sarcoma viral oncogene homolog and epidermal growth factor receptor genes and to rearrangements in the anaplastic lymphoma kinase. Furthermore, activation of hypoxic signaling pathways and the transforming growth factor beta 1 axis can have an impact on the level of PD-L1 expression in NSCLC. A deeper understanding of the complex mechanisms regulating PD-L1 expression is necessary to tailor the treatment with ICI in patients with advanced NSCLC.
In this review, we present an overview of key factors underlying the regulation of PD-L1 expression within the TME of NSCLC, which are, and potentially can be, exploited to improve the outcomes of immunotherapy targeting the PD-1 axis.
Cancer cells need to regulate their metabolic program to fuel several activities, including unlimited proliferation, resistance to cell death, invasion and metastasis. The aim of this work is to ...revise this complex scenario. Starting from proliferating cancer cells located in well-oxygenated regions, they may express the so-called "Warburg effect" or aerobic glycolysis, meaning that although a plenty of oxygen is available, cancer cells choose glycolysis, the sole pathway that allows a biomass formation and DNA duplication, needed for cell division. Although oxygen does not represent the primary font of energy, diffusion rate reduces oxygen tension and the emerging hypoxia promotes "anaerobic glycolysis" through the hypoxia inducible factor-1α-dependent up-regulation. The acquired hypoxic phenotype is endowed with high resistance to cell death and high migration capacities, although these cells are less proliferating. Cells using aerobic or anaerobic glycolysis survive only in case they extrude acidic metabolites acidifying the extracellular space. Acidosis drives cancer cells from glycolysis to OxPhos, and OxPhos transforms the available alternative substrates into energy used to fuel migration and distant organ colonization. Thus, metabolic adaptations sustain different energy-requiring ability of cancer cells, but render them responsive to perturbations by anti-metabolic agents, such as inhibitors of glycolysis and/or OxPhos.
Tumor growth is the orchestration of various oncogenes and tumor suppressors, and the regulation of these genes offers a rational therapeutic approach to cancer treatment. In this study, we found a ...new regulator of tumor growth, phosphatidylinositol 4-kinase type IIα (PI4KIIα), the mechanism of which is involved in angiogenesis and hypoxia-inducible factor HIF-1α regulation. Results obtained from a human cancer tissue microarray showed that PI4KIIα protein expression increases markedly in seven types of cancers compared with normal tissues. Suppression of PI4KIIα leads to retarded tumor growth in nude mice. Downregulation of PI4KIIα in cancer cells eliminates tumor cell-induced endothelial cell tubulogenesis and migration, and results in impaired angiogenesis. Further investigation showed that PI4KIIα can directly regulate HIF-1α expression and that the expression of these two proteins is correlated in vivo. At the same time, downregulation of PI4KIIα markedly reduces HER-2 autophosphorylation, and PI4KIIα specifically triggers HIF-1α accumulation through a phosphatidylinositol 3kinase (PI3K)- and extracellular signal-regulated protein kinase (ERK)-dependent pathway, suggesting that PI4 KIIα may regulate HIF-1α through the HER-2/PI3K, ERK cascade. In summary, we discovered a pivotal role for PI4KIIα in the regulation of tumor growth. Our results shed new light on understanding the novel functions of PI4KIIα in cancer and suggest that PI4KIIα may be a promising specific target for tumor therapy. Oncogene (2010) 29,2550-2559; doi: 10.1038/onc.2010.14; published online 15 February 2010 Keywords: phosphatidylinositol 4-kinase type IIα (PI4KIIα); tumor; angiogenesis; hypoxia-inducible factor-1 a (HIF-1 a)
Polycystic ovary syndrome (PCOS) is a major health problem in reproductive-aged women worldwide, but the precise pathogenesis of PCOS remains unclear. Our previous study revealed that ...hypoxia-inducible factor (HIF)-1a mediated endothelin (ET)-2 signaling plays an important role in ovulation in rats. Therefore, the present study used a PCOS rat model to test the hypotheses that HIF-1a signaling is expressed and inhibited in ovaries during PCOS formation and that the HIF-1a/ET-2 signaling pathway is a target of dimethyldiguanide (DMBG) in the clinical treatment of PCOS. First, the development of a PCOS model and the effect of DMBG treatment were examined through ovarian histology and serum hormone levels, which were consistent with previous reports. Second, HIF-1a and ET-2 expression were detected by immunohistochemistry and western blot. The results showed decreased HIF-1a/ET-2 expression in the ovaries of PCOS rats, whereas DMBG treatment reversed the protein decreases and improved the PCOS symptoms. Third, to understand the molecular mechanism, HIF-1a/ET-2 mRNA expression was also examined. Interestingly, HIF-1a mRNA increased in the ovaries of PCOS rats, while ET-2 mRNA decreased, indicating that HIF-1a protein degradation may be involved in POCS development and treatment. Finally, HIF prolyl hydroxylase (PHD) activity was examined to further clarify the contribution of HIF-1a signaling to the development and treatment of PCOS. The results suggested that the inhibition of HIF-1a/ET-2 signaling may be caused by increased PHD activity in PCOS. DMBG-treated PCOS may further activate HIF-1a signaling at least partly through inhibiting PHD activity. Taken together, these results indicate that HIF-1a signaling is inhibited in a PCOS rat model through increasing PHD activity. DMBG treatment improved PCOS by rescuing this pathway, suggesting that HIF-1a signaling plays an important role in the development and treatment of PCOS. This HIF-1a-mediated ET-2 signaling pathway may be an important mechanism regulating PCOS formation and treatment in mammalian ovaries in vivo and should be a new clinical target for PCOS prevention and treatment in the future.
Malignant cells show increased glucose uptake in vitro and in vivo. This process is considered to be mediated by glucose transporters (GLUTs). Hypoxia-inducible factor-1α (HIF-1α) may upregulate ...GLUT-1 expression. Little is known about the correlation between HIF-1α and GLUT-1 expression in laryngeal carcinoma. The current study investigated this correlation immunohistochemically, according to various clinical and pathological features, in 49 paraffin-embedded archival tissue blocks from patients with laryngeal squamous cell carcinoma. HIF-1α and GLUT-1 expression was detected in 63.3 (31/49) and 55.1% (27/49) of the tumour samples, respectively. HIF-1α expression was significantly correlated with lymph node classification (P=0.018), recurrence (P=0.02) and metastasis (P=0.031). GLUT-1A expression was significantly associated with recurrence (P=0.02) and metastasis (P=0.01). Univariate analyses revealed that HIF-1α (χ2=8.2; P=0.004) and GLUT-1 expression (χ2=9.0; P=0.003) were significantly associated with a poorer survival rate. In a multivariate analysis, GLUT-1 expression (P=0.006) was a significant predictor of poor survival rate, as well as the primary tumour site, lymph node invasion and distant metastasis. Based on Spearman's analysis, GLUT-1 expression and phosphatidylinositol 3-kinase (PI3K) expression were significantly correlated (r=0.504; P=0.000). This is the first study to demonstrate a significant correlation between GLUT-1 and HIF-1α expression in laryngeal carcinoma and to show increased GLUT-1 expression as an independent survival rate predictor. These results suggest that GLUT-1 is a potential new therapeutic target for laryngeal carcinoma.
There is significant evidence that severe tumor hypoxia may cause resistance to chemoradiotherapy and promote metastatic spread in locally advanced carcinoma of the uterine cervix. Some clinical ...investigations have suggested that high expression of hypoxia-inducible factor-1α (HIF-1α) and/or its target gene carbonic anhydrase IX (CAIX) may be useful biomarkers of tumor hypoxia and poor outcome in cervical cancer. Here, we challenged this view by investigating possible associations between HIF-1α expression, CAIX expression, fraction of hypoxic tissue, and lymph node metastasis in experimental human tumors.
Tumors of two cervical carcinoma xenograft lines (CK-160 and TS-415) were included in the study. Pimonidazole was used as a hypoxia marker, and tumor hypoxia, HIF-1α expression, and CAIX expression were detected by immunohistochemistry. Metastatic status was assessed by examining external lymph nodes in the inguinal, axillary, interscapular, and submandibular regions and internal lymph nodes in the abdomen and mediastinum.
Tissue regions staining positive for pimonidazole, HIF-1α, or CAIX were poorly colocalized, both in CK-160 and TS-415 tumors. The expression of HIF-1α or CAIX did not correlate with the fraction of hypoxic tissue in any of the two tumor lines. Furthermore, clinically relevant associations between HIF-1α or CAIX expression and lymph node metastasis were not found.
Because significant associations between HIF-1α expression, CAIX expression, fraction of hypoxic tissue, and incidence of lymph node metastases could not be detected in any of two preclinical models of human cervical cancer, it is not realistic to believe that high expression of HIF-1α or CAIX can be useful biomarkers of tumor hypoxia and poor outcome in a highly heterogeneous disease like cervical carcinoma.
Background: To evaluate the application of blood oxygenation level-dependent (BOLD) imaging and intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) on assessing early ...contrast-induced acute kidney injury (CIAKI). Materials: Sixty rabbits were randomly chosen to undergo iohexol (1.0, 2.5, and 5.0 gI/kg, respectively; n = 15 for each group) or saline injection (n = 15). In each group, 6 rabbits underwent MRI at 24 h before injection and after injection of iohexol or saline (1 h and 1, 2, 3, and 4 days); meanwhile, out of the remaining 9 rabbits, 3 were chosen for MRI acquisition, and then they were killed at specific time points (1 h, 1 day, and 3 days, respectively). Results: The strong attenuation of pure molecular diffusion (D), apparent diffusion coefficient (ADC), and perfusion fraction (f) was observed at 1 day, while pseudodiffusion coefficient (D*) showed a significant decrease at 1 h after iohexol injection. A distinct elevation of apparent transverse relaxation rate (R2*) reached the maximum levels on day 1, which was consistent with the expression of hypoxia-inducible factor-1α and vascular endothelial growth factor. ADC, D, and R2* correlated well with histopathological parameters and biochemical parameters. Conclusion: BOLD combined with IVIM is effective to monitor renal pathophysiology associated with CIAKI.
In this study, the effects of hypoxia-inducible factor-1α (HIF-1α) on gastric carcinoma (GC) drug resistance through apoptosis-related genes are investigated. First, HIF-1α-specific siRNA was ...synthetized and transfected into drug-resistant GC cell line OCUM-2MD3/L-OHP.
Then MTT assay was applied to test the inhibition rate of GC cells by 5-fluorouracil (5-FU) and oxaliplatin (L-OHP). After that, flow cytometry (FCM) was applied to measure apoptosis rate. qPCR and Western blot assay were employed to detect HIF-1α and apoptosis-related genes. Results
showed that HIF-1α in OCUM-2MD3/L-OHP cells was higher than that in OCUM-2MD3 and gastric epithelial cells. After HIF-1α-siRNA transfection, inhibition rates of 5-FU and L-OHP to tumor cells increased significantly. FCM results showed that apoptosis rate of OCUM-2MD3/L-OHP cells
increased significantly. After HIF-1α-siRNA transfection, survivin and Bcl-2 decreased, whereas Bax, caspase 3, and caspase 8 increased significantly. Results from this study seem to confirm that HIF-1α getting involved in GC drug resistance is possibly due to its regulation of
some apoptosis-related genes. HIF-1α may be a potential target to reverse drug resistance of GC.
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