e15023 Background: Long non-coding RNAs (lncRNA) play an important role in many biological processes, and their dysregulation can lead to various diseases, including colorectal cancer (CRC). In recent years, interactions between lncRNA, miRNA and mRNAs in development of CRC have attracted more and more attention. However, the currently obtained data on the complex regulatory interactions between lncRNA and microRNA during metastasis in patients with CRC are fragmentary, often contradictory and obtained on samples that are not significant in size. Therefore, the aim of the study was to analyze the features of lncRNA expression in CRC patients without metastases, with lymph nodes metastases and with liver metastases. Methods: The study included 200 patients with colon adenocarcinoma. The patients were divided into 3 groups: without metastases (T2N0MO, group 1, n = 100), with lymph node metastases (T2-3N1-2M0, group 2, n = 60) and with liver metastases (T3N2M1-2, group 3, n = 40). RNA isolation was performed by guanidine-thiocyanate-phenol-chloroform extraction. The lncRNA list was generated based on bioinformatic analysis. The relative expression of 20 lncRNAs (NEAT1, HELLPAR, AP000766.1, LINC00265, MIRLET7BHG, OLMALINC, AC245884.8, MEOX2-AS1, MEG3, NORAD, HCG11, WASIR2, AC005332.7, PURLN, OIP5-AS1, SNHG14, TUG1, XIST, MALAT1, FAM66E) was evaluated by RT-qPCR method. Differences were assessed using the Mann-Whitney test, and the Bonferroni correction was used to correct multiple comparisons. Results: Differential expression of 5 lncRNA (MALAT1, TUG1, XIST, LINC00265, HELLPAR) was found between CRC patients without metastases and patients with metastases to lymph nodes and liver. Thus, in group 1, expressions of MALAT1, TUG1 and HELLPAR were lower by 2.5, 4.0 and 5.5 times (p < 0.005) than in combined group of patients with metastases to lymph nodes and liver, and XIST and LINC00265 expressions were higher by 2.2 and 3.4 times (p < 0.05), respectively. Differential expression of 2 lncRNA (NORAD, WASIR2) was also found between group 2 and group 3. The NORAD expression in patients in group 3 was 5.5 times (p < 0.05) lower than in patients in group 2, and WASIR2 expression, on the contrary, was 2.5 times (p < 0.05) higher in patients in group 3. Conclusions: Thus, differential expression of lncRNA (MALAT1, TUG1, XIST, LINC00265, HELLPAR, NORAD and WASIR2), associated with regulation of proliferation and invasive ability of tumor cells, was found in 3 groups of CRC patients.
e14502 Background: Currently known markers of lung adenocarcinoma are insufficient to predict the development of this disease, which makes the search for new molecular markers a relevant problem. Our purpose was to analyze changes in genes copy number variation (CNV) in tumor and non-tumor cells of the lung in patients with (T1-3N1-2M0-1) and without (T1-3N0M0) metastasis to identify potential molecular markers for the prediction of the disease development. Methods: The study was performed on tissue sections from FFPE blocks of 90 patients diagnosed with lung adenocarcinoma. Tumor and non- tumor cells were isolated using laser microdissection (Palm MicroBeam, Carl Zeiss). Copy numbers of 32 genes (BAX, BCL2, C-FLAR, P53, MDM2, BFAR, SEMA3B, RASSF1A, CASP9, CASP3, CASP8, SOX2, OCT4, NANOG, PIK3, MKI67, HV2, HIF1A1, XRCC1, MMP1, TERT, CTNNB1, VEGFA, KRAS, EGFR, GRB2, SOS1, MAPK1, STAT1, BRAF, FTO, mir3678) were determined by Real-Time qPCR (ACTB, B2M, GAPDH - reference genes). Statistical analysis was performed using the Mann-Whitney test. Results: A pooled sample (n = 90) showed significant (p < 0.005) increase in the copy numbers of MAPK1 and SOX2 and decreased copy numbers of the mir3678, HV2, BAX and CASP3 genes in tumor cells compared to non-tumor. Patients with metastatic and non-metastatic lung adenocarcinoma had significant (p < 0.05) differences in genes copy number in tumor cells compared to non-tumor ones: patients with T1-3N1-2M0-1 (n = 50) – decreased copy numbers of the mir3678, HV2, MDM2, P53, XRCC1, CASP3 and OCT4 genes and increased SOX2 copy number; patients with T1-3N0M0 (n = 40) – increased copy numbers of the MAPK1 and mir3678 genes and decreased HV2 copy number. Conclusions: The detected changes in copy numbers of genes responsible for the regulation of apoptosis, proliferation, oxidative phosphorylation and the function of the EGFR signaling pathway in lung tumor cells revealed new molecular markers to predict the risk of metastasis ( mir3678, MDM2, Р53, SOX2, XRCC1, CASP3, OCT4, MAPK1).
Purpose of the study. Evaluation of the antioxidant status and DNA damage in tissues of subcutaneous xenografts of non-small cell lung cancer and in peritumoral tissues created using the A549 and H1299 cell cultures.Materials and methods. The study included 35 intact male Balb/c Nude immunodeficient mice. Cell lines A549 and H1299 were used as transplantable tumor biomaterial. A CDX model was created in accordance with the protocol for supratentorial injections (Ozawa T., James C. D., 2010) adapted for this experiment. Growth rates were controlled and intracranial xenografts were visualized using a high-resolution micro-CT system. The activity of catalase and superoxide dismutase was determined with non-denaturing electrophoresis in 8 % and 12 % polyacrylamide gel. The concentrations of sulfhydryl groups were determined according to Ellman. The DNA damage in lymphocytes was determined by the comet assay.Results. The experiment resulted in the creation of models of brain tumors characterized by intracranial growth pattern in 100 %. The activity of catalase in the studied lysates of intracranial xenografts, peritumoral tissue and healthy tissues of tumor-bearing animals in all experimental groups increased statistically significantly relative to the healthy tissue of intact animals, and the greatest differences from the control were recorded in the group of animals with implanted H1299 culture at a concentration of 1 × 106 . Superoxide dismutase activity in the studied lysates of intracranial xenografts and peritumoral tissues statistically significantly increased compared to the control sample in all experimental groups. The highest increase in the SOD activity was observed in the tissues of intracranial xenografts with the highest tumor load, which amounted to 28.8 % and 32.9 % of the changes relative to the control sample. A statistically significant increase in the concentration of SH-groups relative to the control sample in tumor tissue lysates was revealed in all experimental groups, and the highest concentration (36.2 ± 0.47) was observed in the group of experimental animals with the highest tumor load. Percentage change in tail moment (DNA damage indicator) in groups O1, O2, O3 and O4 increased statistically significantly compared to the control sample by 55.8 %, 111.8 %, 97.3 % and 170 %, respectively.Conclusions. The observed increase in the activity of the antioxidant defense system, accumulation of oxidative modifications of proteins, and an increase in DNA double-strand breaks in the tissues of intracranial xenografts of non-small cell lung cancer in vivo suggest that the created models reflect processes similar to those in tumors of human non-small cell lung cancer.
More than 1.8 million of new cases of lung cancer (LC) are registered each year worldwide. LC is the leading cause of cancer death in both developing and developed countries, and the 5 years survival rate is as low as 19 %. Many factors explain such unsatisfactory outcomes, including the LC diagnosis at an advanced stage, when the currently available treatments can rarely provide cure. Biomarkers are used to assess the development risks, screening, diagnosis, monitoring, and prognosis, and to personalize the LC treatment. Clinical use of biomarkers is essential for the identification of a high-risk group for screening for LC and differentiating early LC from benign pulmonary lesions. Current trends in the development of LC biomarkers involve the integration of molecular biomarkers with clinical and radiological characteristics using artificial intelligence for the development of imaging biomarkers, and using highly sensitive technologies such as next-generation sequencing for molecular research. LC biomarkers are now at all stages of development, from discovery to clinical trials requiring high-quality clinical validation. Reliable biomarkers are especially needed to differentiate malignant and benign lesions in the lung tissue and to identify those at greatest risk of developing lung cancer. Scientific advances in understanding LC have led to the development of biomarkers that demonstrate sufficient accuracy in clinical validation studies. Promising trends in the development of LC biomarkers include highly sensitive and increasingly accessible NGS and radiomics technologies, along with the use of easily collected biomaterials, which in combination with other tumor characteristics contribute to the development of biomarkers for assessing the LC development risks, diagnosis, monitoring, prognosis and personalized therapy. This review focuses on the development, current application, and future trends in the use of LC biomarkers.
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