Malignant cell transformation is accompanied by two processes of DNA methylation changes

Bondar, A. A.

Cherdyntseva, Nadezhda V.

Dobrodeev, A. Y.

Laktionov, P. P.

Ponomaryova, Anastasia A.

Rykova, E. Y.

Tuzikov, S. A.

Vlassov, V. V.

Zavyalov, A. A.

English

Tomsk State University Repository

Tomsk National Research Medical Center of the Russian Academy of Sciences National Research Tomsk State University  The 22nd International Charles Heidelberger Symposium on Cancer ResearchProceedings of the International Symposium17–19 September 2018 Publishing house of Tomsk University201888 http://tnimc.ru/upload/publications/proceedings/2018_22_symposium.pdf22ND INTERNATIONAL CHARLES HEIDELBERGER SYMPOSIUM ON CANCER RESEARCHFlotillin overexpression is detected in many invasive carcinoma and sarcoma and is a marker of poor prognosis associated with a higher metastatic risk [4-8]. How flotillins participate in the acquisition of invasive and metastatic properties remains to be determined.Our study aims at identifying how the UFIT pathway influences the membrane remodeling and modifies the trafficking of cargo leading to the acquisition of invasive properties.We show that flotillins downregulation in invasive cancer cells dramatically inhibit their invasive properties as monitored in vitro using a 3D-collagen invasion assay and in vivo using zebrafish xenografts. Reciprocally, ectopic up-regulation of flotillins in non-tumoral cells is sufficient to induce their invasive behavior in vitro and in vivo. We show that flotillins are critical regulators of the trafficking of several cargo amongst them MT1-MMP, a key metalloproteinase responsible for the proteolytic activity of invadopodia [9].Keywords: flotillins, cancer marker, metastasis, cell invasion.REFERENCES1. Bodin S., Planchon D., Rios Morris E., Comunale F., Gauthier-Rouviere C. Flotillins in intercellular adhesion - from cellular physiology to human diseases. J Cell Sci. 2014 Dec 15; 127(Pt 24): 5139-47. doi: 10.1242/jcs.159764.2. Frick M., Bright N.A., Riento K., Bray A., Merrified C., Nichols B.J. Coassembly of flotillins induces formation of membrane microdomains, membrane curvature, and vesicle budding. Curr Biol 2007, 17:1151–1156. doi: 10.1016/j.cub.2007.05.078.3. Glebov O.O., Bright N.A., Nichols B.J. Flotillin-1 defines a clathrin-independent endocytic pathway in mammalian cells. Nat Cell Biol. 2006; 8: 46–54. doi: 10.1038/ncb1342.4. Cao S., Cui Y., Xiao H., Mai M., Wang C., Xie S., Yang J., Wu S., Li J., Song L., Guo X., Lin C. Upregulation of flotillin-1 promotes invasion and metastasis by activating TGF-&beta; signaling in nasopharyngeal carcinoma. Oncotarget. 2016 Jan 26; 7(4): 4252-64. doi: 10.18632/oncotarget.6483.5. Koh M., Yong H.Y., Kim E.S., Son H., Jeon Y.R., Hwang J.S., Kim M.O., Cha Y., Choi W.S., Noh D.Y., Lee K.M., Kim K.B., Lee J.S., Kim H.J., Kim H., Kim H.H., Kim E.J., Park S.Y., Kim H.S., Moon W.K., Choi Kim H.R., Moon A. A novel role for flotillin-1 in H-Ras-regulated breast cancer aggressiveness: Flotillin-1 is Important for Breast Cancer Aggressiveness. Int J Cancer. 2016 Mar 1; 138(5): 1232-45. doi: 10.1002/ijc.29869.6. Liu Y., Lin L., Huang Z., Ji B., Mei S., Lin Y., Shen Z. High expression of flotillin-2 is associated with poor clinical survival in cervical carcinoma. Int J Clin Exp Pathol. 2015; 8: 622–628.7. Li H., Wang R.-M., Liu S.-G., Zhang J.-P., Luo J.-Y., Zhang B.-J., Zhang X.-G. Abnormal expression of FLOT1 correlates with tumor progression and poor survival in patients with non-small cell lung cancer. Tumour Biol. 2014 Apr; 35(4): 3311-5. doi: 10.1007/s13277-013-1434-3.8. Wang X., Yang Q., Guo L., Li X.H., Zhao X.H., Song L.B., Lin H.X. Flotillin-2 is associated with breast cancer progression and poor survival outcomes. J Transl Med. 2013 Aug 15; 11: 190. doi: 10.1186/1479-5876-11-190.9. Castro-Castro A., Marchesin V., Monteiro P., Lodillinsky C., Rosse C., Chavrier P. Cellular and Molecular Mechanisms of MT1-MMP-Dependent Cancer Cell Invasion. Annu Rev Cell Dev Biol. 2016 Oct 6; 32: 555-576. doi: 10.1146/annurev-cellbio-111315-125227.CIRCULATING DNA-MARKERS IN LUNG CANCER: CHANGES IN RETROTRASPOSONS METHYLATION STATUS IN RESPONSE THERAPY AND DURING THE POST-TREATMENT FOLLOw-UPA.A. Ponomaryova1,3, A.Y. Dobrodeev1, A.A. Bondar2, N.V. Cherdyntseva1,4, A.A. Zavyalov1, S.A. Tuzikov1, V.V. Vlassov2, P.P. Laktionov2,5, Е.Y. Rykova2,6Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia1Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia2Tomsk Polytechnic University, Tomsk, Russia3Tomsk State University, Tomsk, Russia4Meshalkin Novosibirsk Research Institute of Circulation Pathology, Novosibirsk, Russia5Novosibirsk State Technical University, Novosibirsk, Russia6BackgroundMalignant cell transformation is accompanied by two processes of DNA methylation changes: hypermethylation in CpG islands of tumor suppressor genes and global hypomethylation in repeti-tive DNA sequences (retrotransposons) [1, 2]. The composition of circulating DNA (cirDNA) from plasma and cell-surface-bound cirDNA (csb-cirDNA) was shown earlier to be altered in the blood of cancer patients due to accumulation of tumor-specific aberrantly methylated DNA fragments, which are currently considered valuable cancer markers [3, 4].Material and MethodsThe present study compared LINE-1 retrotransposon methylation patterns in free-cirDNA and csb-cirDNA from healthy subjects (n=33) and lung cancer (LC) (n=32) patients, and also from 8917–19 September, 2018PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUMLC patients during the post-treatment follow-up period. Concentrations of methylated LINE-1 region 1 (LINE-1met) were assayed by real-time methylation-specific PCR. In order to normal-ize the LINE-1 methylation level, the LINE-1 region 2 concentration was evaluated, which was independent of the methylation status (LINE-1Ind).ResultsThe LINE-1 methylation level, determinated as the ratio LINE met/LINE Ind, in csb-cirDNA from LC patients was significantly lower than in csb-cirDNA from healthy subjects (P=0.005). In the total group of LC patients, LINE-1 methylation level was shown to be significantly increased during the follow-up after chemotherapy (P<0.05, paired test) and after surgery comparaed to the methylation level before treatment (P<0.05, paired t-test). The revealed association between LINE-1 methylation level and effect of antitumor therapy was more pronounced in squamous cell lung cancer compared with adenocarcinoma (P<0.05 and P>0.05, respectively). All relapse-free patients within the follow-up period (n=19) were characterized by an increase in LINE-1 methylation level, and patients who experienced disease recurrence (n=13) had decreased levels that corresponded to those observed before treatment.ConclusionOur data demonstrate that LINE-1 methylation level determination represents a valuable tool for evaluation of cancer treatment efficiency and post-treatment monitoring.Keywords: lung cancer, diagnosis, prognosis, oncomarkers, methylation, circulating DNA.The study was supported by the fundamental research program of the Presidium of the Russian Academy of Sciences «Fundamental research for the development of biomedical technologies» (2014-208), the program of the Presidium of the Russian Academy of Sciences «Molecular and Cellular Biology», the Russian Foundation for Basic Research (№ 17-29-06002), scholarship of the RF President (№ SP-1549.2018.4; 2018-2020).REFERENCES1. Plongthongkum N., Diep D.H., Zhang K. Advances in the profiling of DNA modifications: cytosine methylation and beyond. Nat Rev Genet. 2014 Oct; 15(10): 647-61. doi: 10.1038/nrg3772.2. Warton K., Mahon K.L., Samimi G. Methylated circulating tumor DNA in blood: power in cancer prognosis and response. Endocr Relat Cancer. 2016 Mar; 23(3): R157-71. doi: 10.1530/ERC-15-0369.3. Rykova E.Y., Morozkin E.S., Ponomaryova A.A., Loseva E.M., Zaporozhchenko I.A., Cherdyntseva N.V., Vlassov V.V., Laktio-nov P.P. Cell-free and cell-bound circulating nucleic acid complexes: mechanisms of generation, concentration and content. Expert Opin Biol Ther. 2012 Jun; 12 Suppl 1: S141-53. doi: 10.1517/14712598.2012.673577.4. Ponomaryova A., Rykova E., Cherdyntseva N., Skvortsova T., Dobrodeev A, Zav’yalov A., Bryzgalov L., Tuzikov S., Vlassov V., Laktionov P. Potentialities of aberrantly methylated circulating DNA for diagnostics and post-treatment follow-up of lung cancer patients. Lung Cancer. 2013 Sep; 81(3): 397-403. doi: 10.1016/j.lungcan.2013.05.016.AUTOMATED IMAGE ANALYSIS IN ASSESSMENT OF E-CADHERIN DOwN-REGULATION DURING EPITHELIAL-MESENCHYMAL TRANSITION IN PROSTATE CANCERM. PuchinskayaMinsk City Clinical Oncologic Dispensary, Minsk, BelarusExperience of using automated image analysis with Aperio software for evaluation of E-cadherin expression is presented. Advantages and limitations of the method are described. Automated analysis makes it possible to distinguish changes in marker expression that may be difficult to assess visually.Keywords: automated image analysis, Aperio, E-cadherin, epithelial-mesenchymal transition.Automated image analysis (AIA) is becoming increasingly popular in pathology as it provides some opportunities that are difficult or even impossible to realize by visual staining assessment [1-3]. It is used for a wide variety of applications, but, anyway, can’t yet substitute classic pathology.During epithelial-mesenchymal transition (EMT) epithelial cells transiently acquire some features of mesenchymal ones, this leads to higher invasion, migration and therapeutic resistance. 

Circulating DNA-markers in lung cancer: changes in retrotrasposons methylation status in response therapy and during the post-treatment follow-up

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Circulating DNA-markers in lung cancer: changes in retrotrasposons methylation status in response therapy and during the post-treatment follow-up

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