Non-small cell lung cancer (NSCLC) is prevalent worldwide and has a high mortality rate. Even if mesenchymal stem cells (MSCs) are suggested as cancer treatment, the studies of their effects on NSCLC cells contradict each other, mainly due to utilization of two-dimensional (2D) culture system. Three-dimensional (3D) culture systems resemble tissue organization in vivo. Here we comprehensively explore the inhibitory effects of MSCs on NSCLC cells in a 3D culture system. We confirmed that the inhibitory effects of 3D-cultured MSCs (3D-MSCs) on the proliferation and migration of NSCLC cells are greater than that of the 2D-cultured MSCs. 3D-MSCs overexpress IL-24, which serve as the key factor enhancing antitumor effects of MSCs. In these cells, IL-24 affects p38 MAPK and CXCR4/AKT pathways. Overall, this study provides the support for use of MSCs in tumor.

Collagens are the main components of human tissues. Various regulatory factors and cytokines may influence expression levels for collagen-encoding genes, and, therefore, contrubite to some collagen-associated pathologies. In this study, we demonstrate regulatory effects of USF1 on expression of genes encoding fibrillar collagen types I, II, and III in osteoblastic Saos-2 and MG-63 cells. An ectopic expression of the human USF1 led to a decrease in both mRNA and protein expression levels of the collagen-encoding genes mentioned above. ADAMTS-3 is a proteinase primarily responsible for the amino-terminal cleavage of type I and type II collagen precursors. The ADAMTS-3 promoter region contains potential binding sites for USF1. Here we show that an overexpression of USF1 lead to a decrease in ADAMTS-3 mRNA and protein expression levels. In co-transfection studies, USF1 negatively regulated ADAMTS-3 promoter activity. Further, in EMSA studies, we showed that USF1 binds to the ADAMTS-3 promoter region. In conclusion, it seems that ADAMTS-3 and USF1 contribute to the regulation of collagen encoding genes in osteosarcoma.

Autophagy is an evolutionarily conserved cellular process in which components of the cytoplasm are delivered to lysosomes for degradation and has been proposed to play a role in imatinib resistance in chronic myeloid leukemia cells. Chronic myeloid leukemia is a clonal myeloproliferative disorder arising from the neoplastic transformation of the hematopoietic stem cell. We used a Bcr-Abl-independent and imatinib-resistant K562 subpopulation (K562-IR) that we generated earlier in our laboratory for this study. We showed that in the presence of imatinib autophagy was triggered via LC3I/II transformation, p62 protein expression and acidic vacuoles accumulation in tyrosine kinase inhibitor-sensitive K562 cells; whereas in the cell line K562-IR which is imatinib-resistant and Bcr-Abl independent, autophagy is not triggered. With ongoing research and trails to combine tyrosine kinase inhibitors with autophagy inhibitors, our results suggest a model of resistance in which treatment with a TKI inhibitor does not increase autophagy, basically because its presence does not cause cellular stress due to Bcr-Abl signaling not being required for survival.

Tumor-specific promoters and cis-regulatory genetic elements are used for transcriptional control of therapeutic transgene expression in cancer gene therapy. HRE (hypoxia response element) and ARE (anti-oxidant response elements) cis-regulatory elements are targets for HIF1 and Nrf2 transcriptional factors, respectively, and mediate activation of gene transcription in a response to hypoxia and oxidative stress, characteristic of most solid tumors. Due to these features HREs and AREs are used in genetic constructs for cancer gene therapy to provide tumor-specific therapeutic transgene expression or replication of oncolytic adenovi-ruses. In this work on the basis of the tumor-specific promoter hTERT we have constructed hybrid promoters carrying combinations of HRE and ARE. We showed that upon imitation of hypoxia in human lung cancer cell lines the activity of the hybrid promoter HRE-ARE-hTERT is substantially higher compared to promoters carrying only ARE or HRE. Using in vitro suicide cancer gene therapy with the CD: UPRT/5-FC (cytosine deaminase; uracil phosphoribosyl transferase/5-fluorocytosine) enzyme-prodrug system as a model we showed an enhancement of the cytotoxic effect on human lung cancer cells upon imitation of hypoxia when cytosine deaminase: uracil phosphoribosyl transferase was expressed under the control of the HRE-ARE-hTERT promoter compared to HRE-hTERT and ARE-hTERT promoters. The novel hybrid promoter HRE-ARE-hTERT could be used for transcriptional targeting of therapeutic transgene expression or oncolytic adenovirus replication upon development of novel anti-cancer gene therapeutics.

Recently, a wealth of data have been accumulating on the role of long non-coding RNAs (lncRNAs) in the fine-tuning of mRNA expression. Four new lncRNAs, namely, TMEM92-AS1, FAM222A-AS, TXLNB, and lnc-CCL28, were identified as differentially expressed in ovarian tumors using deep machine learning. The levels of lnc-CCL28 transcripts in both tumors and normal tissue samples were sufficient for further analysis by RT-PCR. In addition, the promising ovarian cancer biomarkers, lncRNAs LINC00152, NEAT 1 and SNHG17 were added to RT-PCR analysis. For the first time, an increase in the level of lnc-CCL28 and SNHG 17 lncRNAs was found in ovarian tumors, and the overexpression of LINC00152 and NEAT1 was confirmed. It seems that lnc-CCL28 is involved in carcinogenesis and, in particular, in ovarian cancer progression. Overexpression of LINC00152 and lnc-CCL28 was significantly associated with the later stages and metastasis.

Small SCP phosphatases CTDSP1, CTDSP2, and CTDSPL specifically dephosphorylate serine and threonine residues in protein molecules. The enzymes are involved in regulating activity of RNA polymerase II at the transition from transcription initiation to elongation, regulating expression of neuron-specific genes, and activating the key cell-cycle protein pRb at the G1/S boundary. In addition, the substrates of SCP phosphatases include SMAD transcription modulators; AKT1 protein kinase, which regulates the cell cycle, apoptosis, and angiogenesis; the TWIST1 and c-MYC transcription factors; Ras family proteins, which are involved in signaling pathways regulating the cell growth and apoptosis; CDCA3, which is associated with cell division; the cyclin-dependent kinase inhibitor p21; and the promyelocytic leukemia protein (PML), which is involved in regulation of the tumor suppressors p53, PTEN, and mTOR. Dysfunction or inactivation of SCP phosphatases leads to various diseases, including cancer. Recently the increase in interest to SCP phosphatases is due to their their tumor growth-inhibiting properties or role in the development of malignant tumors of various etiology and localization. The review discusses the properties of SCP phosphatases and their role in oncogenesis. Understanding the functions of SCP phosphatases and their regulatory mechanisms can be useful in searching for efficient targets for tumor therapy.

The oxytocin receptor (OXTR) plays an important role in childbirth, breastfeeding, and social interactions. There is emerging evidence that OXTR is associated with the breast cancer (BC) initiation and progression. However, the mechanisms leading to a change in its expression, the diagnostic or prognostic value of the receptor in BC are currently poorly understood. Here, we have evaluated the relative level of OXTR expression in BC samples (n=107), and also investigated the effect of estradiol on its expression in MCF-7 and MDA-MB-231 cells. The level of OXTR expression was significantly lower in breast tumor tissue than in normal tissue obtained from the same patient. The expression of OXTR was dependent on the status and expression of the estrogen receptor (ER): the level of OXTR mRNA was significantly lower in ER-negative BC samples compared to ER-positive BC samples. Moreover, OXTR expression was also lower in samples from patients with luminal subtype with a low value of ER expression (0-5 score according to the IHC assay, Allred scoring) compared with samples with high ER expression (6-8 score). In luminal BC, OXTR expression was associated with the HER2 expression level: the OXTR mRNA level was higher in tumors with a HER2 IHC score of 1+ as compared to cases with the HER2 expression score of 2+, 3+. We also showed that estradiol increased the level of OXTR mRNA in MCF-7 cells, but not in ER-negative MDA-MB-231 cells. These data indicate that changes in OXTR expression in BC tissues can be caused by increased ER expression. We found no association between OXTR and T or N stages and progesterone receptor expression.

LiFraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary disorder that is characterized by an increased risk for certain types of cancer, acute lymphoblastic leukemia (ALL), particularly. Germline TP53 mutations are associated with LFS. Genetic counseling and follow-up is essential for patients with LFS and their relatives. Special therapeutic approaches are needed for treatment of oncological disease in these patients. The article presents a series of clinical cases of patients with ALL and SLF, considers general issues of diagnosis and treatment of adult patients with this hereditary genetic syndrome.

To analyze the results of treatment in patients with acute myeloid leukemia (AML) within protocols AML-17 and modified AML-17 (mOML-17) as part of two consecutive pilot studies in order to develop the best treatment strategy for AML patients aged below 60 years.

Gastric cancer is one of the leading causes of cancer morbidity and mortality worldwide. It is common practice to use two classification systems: the Lauren classification system and the WHO classification of tumors in the morphological study of gastric carcinomas. Since 2010, the WHO classifications have included the term "poorly cohesive carcinoma", which refers to all diffuse forms of gastric cancer, including signet ring cell carcinoma and other subtypes. Despite this, the term has not been widely used in the world community, and it is almost not found in Russian literature. Only recently, after the publication of the 5th edition of the WHO classification (2019), there have been review articles where the term is used, but its name can be translated into Russian in different ways: poor-, weak -, low-adhesive, discogesive. The paper analyzes the Pubmed and Elibrary databases in order to find out the frequency of using various designations for diffuse gastric carcinoma, justifies the use of the term «poorly cohesive carcinoma», and proposes a variant of the term interpretation in Russian.

Mutations in the C-KIT gene encoding type III receptor tyrosine kinase that regulates cellular processes, such as differentiation, survival, proliferation, migration, and apoptosis, are found in some neoplasms: gastrointestinal stromal tumor, mastocytosis, melanoma, breast carcinomas, myeloid leukemias, and a number of others. Tumors that exhibit these mutations are sensitive to therapy with tyrosine kinase inhibitors, which makes it necessary to correctly identify the mutation status by C-KIT in order to apply a personalized approach to therapy. This literature review shows that the type and localization of the C-KIT gene mutation are of crucial prognostic value and significance in choosing drugs for antitumor therapy, but traditional diagnostic methods fail to determine accurate mutation characteristics. Routine sequencing techniques focus on identifying the gene mutations associated with specific cellular processes, such as DNA damage and repair. The emergence of next-generation sequencing techniques has solved this problem, making it possible to fully analyze the genome of a malignant neoplasm, with constant screening for new mutations that appear as the tumor develops, affect the prognosis of the disease, and change its sensitivity to the antitumor therapy.

Tumor budding was declared as independent prognostic factor for early cancer in 2016. Tumor-associated fibroblasts (CAFs) are one of the main components of tumor microenvironment. Plenty of different markers are used for detection of CAFs, including podoplanin (POD).

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with average survival time of 15 months. Less than 2% of the patients survive beyond 36 months. To understand the molecular mechanism responsible for poor prognosis, we analyzed GBM samples of TCGA microarray (n=560) data. We have identified 720 genes that have a significant impact upon survival based on univariate cox regression. We applied the Genome Enhancer pipeline to analyze potential mechanisms of regulation of activity of these genes and to build gene regulatory networks. We identified 12 transcription factors enriched in the promoters of these genes including the key molecule of GBM - STAT3. We found that STAT3 had significant differential expression across extreme survivor groups (short-term survivors- survival 36 months) and also had a significant impact on survival. In the next step, we identified master regulators in the signal transduction network that regulate the activity of these transcription factors. Master regulators are filtered based on their differential expression across extreme survivors groups and impact on survival. This work validates our earlier report on master regulators IGFBP2, PDGFA, OSMR, and AEBP1 driving short survival. Additionally, we propose CD14, CD44, DUSP6, GRB10, IL1RAP, FGFR3, and POSTN as master regulators driving poor survival. These master regulators are proposed as promising therapeutic targets to counter poor prognosis in GBM. Finally, the algorithm has prioritized several drugs for the further study as potential remedies to conquer the aggressive forms of GBM and to extend survival of the patients.

Molecular profiling of tumors may provide promising options for personalized treatment. We have examined the spectrum of germline and somatic mutations in 23 breast cancers (ВС) of various molecular subtypes, including tumors 1) with expression of estrogen, progesterone and/or epidermal growth factor receptor HER2/neu, and 2) with a triple negative phenotype. Genomic DNA specimens were isolated from archived tumor and normal tissue samples and subjected to targeted sequencing of the coding regions of 25 cancer-associated genes with a mean coverage of x 1000. In the triple negative subtype of ВС, the pathogenic germline mutations BRCA1 c.66_67delAG (185delAG) and BRCA1 c.3226_3227AG (3347delAG) were detected, while the germline mutation BRCA2 658_659del (886delGT) was found in patients with positive receptor staining. Mutations in BRCAl/2 were overrepresented by frequency (80%), pointing at common loss of heterozygosity affecting the normal allele. Somatic mutations in the TP53 gene were found in 7/10 (70%) patients with the triple negative subtype of ВС and in 3/13 (23%) in the group with positive receptor staining. Additionally, in both groups of patients, somatic mutations of the PTEN, MSH2, MSH6, and MUTYH genes were detected.

The HBV-related hepatocellular carcinoma (HCC) is an important liver malignancy worldwide and carries a poor prognosis. In this regard, an accurate diagnosis is necessary to enable successful treatment. The aim of the current study was to assess the relationship between the expression of certain molecular markers and HCC diagnosis in Iran. Immunohistochemistry and quantitative RT-PCR techniques were used to evaluate the expression patterns of p53 and Ki-67 in liver tissues from 121 HCC and/or HBV-infected patients and 30 healthy volunteers. Patients with HBV+HCC demonstrated increased expression of both p53 and Ki-67 compared to patients with HBV only, highlighting correlation between the p53 and Ki-67 expression levels and HCC diagnosis. The prognostic value of p53 for the diagnosis of HCC was more reliable. The p53 demonstrated higher sensitivity compared to the Ki-67 (sensitivity and specificity, 77.3 and 76.4% for the p53, and 51.0 and 97.9% for the Ki-67, respectively). A panel containing two positive markers had higher specificity and comparable sensitivity to a panel with one positive marker regardless of which one (sensitivity and specificity, 94.8 and 97.9%, for two positive markers and 96.5 and 86.4% for one positive marker, respectively). Taken together the combined analysis of p53 and Ki-67 expression provides a mean to increase the specificity and sensitivity of HBV-related HCC diagnosis to an acceptable level.

Birt-Hogg-Dubé syndrome is a rare autosomal dominant disease caused by a mutation in the FLCN gene and presents with a triad of multiple fibrofolliculomas, trichodiscomas, and masses that clinically resemble fibroepithelial polyps (acrochordones), accompanied by an increased risk of kidney tumors and lung cysts. The paper provides a literature review supplemented by clinical cases and the morphological pattern of skin lesions. It presents the clinical and morphological features of cutaneous manifestations of the syndrome and gives diagnostic criteria.

Certain difficulties arise in the differential diagnosis between Reed nevus that is common in children and adolescents and cutaneous melanoma that is extremely rare in patients of this age group. In addition to the classical histological examination, an immunohistochemical test for marker proteins is carried out to improve the accuracy of the diagnosis of pigmented skin neoplasms.

To determine the level of E-cadherin expression in tumor emboli, to compare it with expression in a tumor, to determine the dependence of E-cadherin expression in tumor emboli on the clinical and morphological characteristics of gastric cancer.

Triple negative breast cancer (BC) is a heterogeneous group of carcinomas that substantially differ in clinical, morphological, and molecular genetic characteristics, tumor response to chemotherapy, and prognosis. These features define triple negative BC today as a special clinical problem that has not yet been completely solved. The review is devoted to the description and systematization of the currently available literature data concerning molecular and genetic features and differences in a fairly significant group of breast carcinomas with a severe, aggressive course and an extremely poor prognosis. The review presents the existing molecular genetic classification of triple negative BC based on the results of studies conducted by M.D. Burstein (2015) and B.D. Lehmann (2016), which determines the presence of 4 tumor-specific subtypes: basal-like type (type 1 and type 2), mesenchymal, and luminal androgen receptor types. The paper reflects the main stages of transformation of the proposed classification over the past decade and an attempt has been make to describe the molecular characteristics of each subtype of these carcinomas.

Adrenocortical cancer (ACC) is a rare endocrine malignancy of the adrenal cortex, which has an unfavorable prognosis and extremely aggressive clinical behavior in most cases. Nevertheless, cases of a more favorable disease course with late metastasis and slow progression have been described. In 2017, the International Agency for Research on Cancer (IARC) and the World Health Organization (WHO) in the 4th edition of the Classification of Tumors of the Endocrine Organs identified histological variants of ACC, such as classical, oncocytic, myxoid, and sarcomatoid ones, indicating the morphological heterogeneity of this tumor.