TLR family gene expression in relation to the HIF1α and the VEGFR pathway activation in endometrial cancer
, 2, 1, 1, 1, 2
Abstract
Introduction: Malignant neoplasm of the endometrium is the most common malignant neoplasm of the female reproductive system. Toll Like Receptors (TLR) play a significant role in innate and late-immunity against infections or damaged tissues. TLRs are also involved in the development of tumors in their natural microenvironment. TLRs play an important role in angiogenesis, necessary for survival and growth of the tumor. Hypoxia playing a critical role in angiogenesis, carcinogenesis, tumor progression and distant metastasis is primarily mediated through hypoxia inducible factors (HIFs). Vascular endothelial growth factor family proteins (VEGF) are also strongly involved in tumor angiogenesis and their action is strongly associated with TLR receptors.
Objectives: The aim of the study was to correlate the expression of selected TLRs and VEGFR’s as well as HIF1α with clinicopathological data of endometrial cancer patients. Material and methods: 123 neoplastic endometrial samples were included in the study. 51 samples of healthy endometrium served as control. The expression of TLR1, TLR2, TLR3, TLR4, VEGFR1 and VEGFR2, VEGF-A and HIF1α was examined after RNA isolation at the mRNA level by Real Time-PCR.
Results: We have noted a significant correlation between the expression of selected TLR and VEGFR’s and clinical stage as well as pathological grading of endometrial cancer.
Conclusions: Received correlations confirm a significant contribution of some TLR expression and the receptor for VEGF in the pathogenesis of epithelial endometrial cancer.
Keywords: endometrial cancerTLR familyVEGFVEGR2VEGFR1HIF1-α
References
- Łuczak MW, Roszak A, Pawlik P, et al. Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced uterine cervical carcinoma. Oncol Rep. 2011; 26(5): 1259–1264.
- Yu Li, Wang L, Chen S. Endogenous toll-like receptor ligands and their biological significance. J Cell Mol Med. 2010; 14(11): 2592–2603.
- Clarke DL, Davis NHE, Majithiya JB, et al. Development of a mouse model mimicking key aspects of a viral asthma exacerbation. Clin Sci (Lond). 2014; 126(8): 567–580.
- Nadeem A, Siddiqui N, Al-Harbi NO, et al. TLR-7 agonist attenuates airway reactivity and inflammation through Nrf2-mediated antioxidant protection in a murine model of allergic asthma. Int J Biochem Cell Biol. 2016; 73: 53–62.
- Netea MG, Van Der Graaf CAA, Vonk AG, et al. The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J Infect Dis. 2002; 185(10): 1483–1489.
- van der Heijden IM, Wilbrink B, Tchetverikov I, et al. Presence of bacterial DNA and bacterial peptidoglycans in joints of patients with rheumatoid arthritis and other arthritides. Arthritis Rheum. 2000; 43(3): 593–598, doi: 10.1002/1529-0131(200003)43:3<593::AID-ANR16>3.0.CO;2-1.
- Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008; 27(45): 5904–5912.
- Li H, Han Y, Guo Q, et al. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol. 2009; 182(1): 240–249.
- Strauss L, Bergmann C, Whiteside TL. Human circulating CD4+CD25highFoxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis. J Immunol. 2009; 182(3): 1469–1480.
- Yusuke S, Yasufumi G, Norihiko N, et al. H.: Cancer Cells Expressing Toll-like Receptors and the Tumor Microenvironment. Cancer Microenvironment. 2009; 2(Suppl 1): 205–214.
- Zhou M, McFarland-Mancini MM, Funk HM, et al. Toll-like receptor expression in normal ovary and ovarian tumors. Cancer Immunol Immunother. 2009; 58(9): 1375–1385.
- Dan HC, Sun M, Kaneko S, et al. Role of X-linked inhibitor of apoptosis protein in chemoresistance in ovarian cancer: possible involvement of the phosphoinositide-3 kinase/Akt pathway. Drug Resist Updat. 2002; 5(3-4): 131–146.
- Kim WY, Lee JW, Choi JJ, et al. Increased expression of Toll-like receptor 5 during progression of cervical neoplasia. Int J Gynecol Cancer. 2008; 18(2): 300–305.
- Lee JW, Choi JJ, Seo ES, et al. Increased toll-like receptor 9 expression in cervical neoplasia. Mol Carcinog. 2007; 46(11): 941–947.
- Xu X, Yan Y, Xun Q, et al. Combined silencing of VEGF-A and angiopoietin-2, a more effective way to inhibit the Ishikawa endometrial cancer cell line. Onco Targets Ther. 2019; 12: 1215–1223.
- Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology. 2005; 69 Suppl 3: 4–10.
- Li H, Han Y, Guo Q, et al. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol. 2009; 182(1): 240–249.
- Lotze MT, Zeh HJ, Rubartelli A, et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol Rev. 2007; 220: 60–81.
- Martins TM, Muniz CS, Andrade VB, et al. Changes in endometrial transcription of TLR2, TLR4, and CD14 during the first-week postpartum in dairy cows with retained placenta. Theriogenology. 2016; 85(7): 1282–1288.
- Tian Q, Xue Y, Zheng W, et al. Overexpression of hypoxia-inducible factor 1α induces migration and invasion through Notch signaling. Int J Oncol. 2015; 47(2): 728–738.
- Allhorn S, Böing C, Koch AA, et al. TLR3 and TLR4 expression in healthy and diseased human endometrium. Reprod Biol Endocrinol. 2008; 6: 40.
- Grimmig T, Moench R, Kreckel J, et al. Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer. Int J Mol Sci. 2016; 17(12).
- Gu CJ, Xie F, Zhang B, et al. High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion. Cell Physiol Biochem. 2018; 50(2): 706–720.
- Mahecha AM, Wang H. The influence of vascular endothelial growth factor-A and matrix metalloproteinase-2 and -9 in angiogenesis, metastasis, and prognosis of endometrial cancer. Onco Targets Ther. 2017; 10: 4617–4624.
- Wang J, Taylor A, Showeil R, et al. Expression profiling and significance of VEGF-A, VEGFR2, VEGFR3 and related proteins in endometrial carcinoma. Cytokine. 2014; 68(2): 94–100.
- Giatromanolaki A, Sivridis E, Brekken R, et al. The angiogenic ?vascular endothelial growth factor/flk-1(KDR) receptor? pathway in patients with endometrial carcinoma. Cancer. 2001; 92(10): 2569–2577, doi: 10.1002/1097-0142(20011115)92:10<2569::aid-cncr1609>3.0.co;2-3.
- Tawadros AI, Khalafalla MM. Expression of programmed death-ligand 1 and hypoxia-inducible factor-1α proteins in endometrial carcinoma. J Cancer Res Ther. 2018; 14(Supplement): S1063–S1069.
