CircLIFRSA/miR-1305/PTEN axis attenuates malignant cellular processes in non-small cell lung cancer by regulating AKT phosphorylation.

BACKGROUND: Non-small cell lung cancer (NSCLC) is typically diagnosed at advanced stages, which limits the effectiveness of therapeutic interventions. The present study aimed to explore the role of the newly identified circLIFRSA in the PTEN/AKT signaling pathway and its involvement in the malignant processes of NSCLC. METHODS: CircLIFRSA expression was identified through microarray analysis, and its levels in NSCLC samples were quantified by RT-qPCR. The impact of circLIFRSA on cell growth, proliferation, apoptosis, and cell cycle were evaluated by MTT assay, colony formation assay, and flow cytometry. Additionally, Western blotting was employed to analyze the expression of PTEN and phosphorylated AKT (pAKT) in NSCLC cells. RESULTS: The expression of circLIFRSA was found to be significantly reduced in NSCLC cells and tissues. This downregulation correlated with various clinicopathological characteristics and indicated its potential as an early diagnostic biomarker for NSCLC. Importantly, circLIFRSA was shown to inhibit cell growth and proliferation while promoting apoptosis in NSCLC cells. Mechanically, circLIFRSA was found to attenuate the malignant processes of NSCLC cells via the miR-1305/PTEN axis and the suppression of AKT phosphorylation. CONCLUSIONS: These findings indicate that circLIFRSA/miR-1305/PTEN axis attenuates malignant processes by regulating AKT phosphorylation, and provide new insights into the potential of circLIFRSA as a biomarker for early diagnosis and as a promising therapeutic target in NSCLC.

Long non-coding RNA LINC00930 targeting miR-6792-3p/ZBTB16 regulates the proliferation and EMT of pancreatic cancer.

Emerging evidence suggests the dysregulation of long non-coding RNAs (lncRNAs) involved in pancreatic cancer (PC). However, the function of LINC00930 in PC has not been elaborated. In this study, we found that LINC00930 was significantly down-regulated in PC cell lines and tissues, and associated with tumor size, lymphatic metastasis, TNM stage and poor prognosis. According to the bioinformatics database, the downregulation of LINC00930 was a common event in PC associated with prognosis and EMT. Overexpression of LINC00930 inhibited the aggressive cancer phenotypes including proliferation, metastasis and epithelial-mesenchymal transition (EMT) of PC in vitro and in vivo. Bioinformatics and dual-luciferase reporter assay indicated that miR-6792-3p could directly bind to LINC00930. Additionally, the Zinc finger and BTB domain containing 16 (ZBTB16) was significantly declined in PC, which was predicted to be the downstream gene of miR-6792-3p. MiR-6792-3p mimic rescued the decreased proliferation, metastasis and EMT caused by ZBTB16 in PC cells. The LINC00930/miR-6792-3p/ZBTB16 axis was associated with the malignant progression and process of PC. The relative expression of LINC00930 was negatively correlated with the expression of miR-6792-3p and was closely linked with ZBTB16 levels in PC. LINC00930 might serve as a potential prognostic biomarker and therapeutic target for PC.

circ0005027 Acting as a ceRNA Affects the Malignant Biological Behavior of Hypopharyngeal Squamous Cell Carcinoma by Modulating miR-548c-3p/CDH1 Axis.

Hypopharyngeal squamous cell carcinoma (HSCC) is a malignant tumor of head and neck. It was verified that circ0005027 was downregulated in HSCC tissues. Here, we aimed to investigate the function and specific regulatory mechanism of circ0005027 in HSCC. Ten pairs tissues of HSCC and adjacent para-cancer were collected. Reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) measured circ0005027, miR-548c-3p, and Cadherin 1 (CDH1) mRNA expression. CCK-8 analyzed cell proliferation viability. Flow cytometry assay detected cell cycle and apoptosis rate. Clonal formation assay measured the clonal ability. Transwell detected cell invasion ability. Western blot was performed to detect CDH1, LAST1, p-LAST1, MST1, p-MST1, YAP1, p-YAP1, TAZ and p-TAZ protein level. Dual-luciferase, RIP and RNA pull-down assay identified the target relationship among circ0005027, miR-548c-3p and CDH1. circ0005027 was decreased in tissues and FaDu cells of HSCC. Overexpression of circ0005027 inhibited cell viability, G1-S transition, clonal formation, and invasion and increased cell apoptosis. circ0005027 acted as a ceRNA and decreased circ0005027 enhanced the malignant process of FaDu cells through sponging miR-548c-3p and inhibiting CDH1 expression. Overexpression of CDH1 activated YAP1/TAZ pathway and inhibited the growth of HSCC in vitro. circ0005027 might act as a potential biomarker for the progression and prognosis prediction in HSCC by regulating miR-548c-3p/CDH1/ YAP1/TAZ signaling pathway.

Molecular genetic tests in survival factors in patients with NSCLC in the clinical practice of Kazakhstan.

Background: Recent changes in understanding of the nature of cancer allow us, in some cases, to consider it a chronic process that requires constant or periodic treatment. The purpose of this study was to assess the efficacy of the methods for diagnosis and treatment of non-small cell lung cancer (NSCLC) in the Republic of Kazakhstan and present scientifically proven methods for the improvement of existing diagnostic algorithms and treatment programs. Methods: This work was a retrospective study. A retrospective study using descriptive and analytical statistics was used as the main method. Reported data and medical records of the patients with NSCLC who were treated from 2015 to 2017 in 6 oncology clinics in the Republic of Kazakhstan were used as study materials. The methods used for histological studies and influence of the patient's sex on the frequency of various histological forms of NSCLC were studied. Polymerase chain reaction (PCR) studies to determine the epidermal growth factor receptor (EGFR) gene status as well as surgical methods were also studied. Results: A comparative analysis of the compliance of oncologists from various regions of the republic with molecular genetic testing as an essential component of the diagnosis of NSCLC showed that the coverage of patients with immunohistochemical (IHC) and PCR studies in this country is low, 50.9% and 21.2%, respectively. The study included data on 423 patients. At the same time, the majority of studies, 64.2% (IHC) and 100% (PCR), were performed in patients in Almaty and only 35.8% of IHC studies were performed in other 5 regions included in this study. Conclusion: The morphological verification of malignant neoplasms in the lungs was based on histological studies. IHC and PCR coverage of the patients in the country was low. Most of the patients received pharmacotherapy. Surgical interventions were rarely performed. Also, the lack of IHC status data were a risk factor for the patients with NSCLC.

Lipid peroxidation functional state changes in patients with obstructive jaundice depending on the level of bilirubin in the blood.

Obstructive jaundice (OJ) is the most common syndrome among diseases of the hepatopancreatoduodenal region and is found in 12-45% of cases. OJ may be benign and malignant etiology. Despite the evidence of the participation of bilirubin in reducing the bactericidal properties of neutrophils, there are no data currently on changes in the functioning of the antioxidant defense system depending on the level of bilirubin in the blood of patients with OJ of various origins. Research in this direction reveals the possibility for the development of pathogenetic recommendations for influencing these links of the pathogenesis of the disease. The study included men with OJ of non-malignant (OJNMG) (n = 47; mean age - 52.02 ± 5.18 years) and OJ of malignant genesis (OJMG) (I-II stages of the malignant process) (n = 45; mean age - 53.02 ± 4.8 years), divided into three subgroups, depending on the level of bilirubin in the blood. The indicators of practically healthy men as a control (n = 50, average age - 48.7 ± 3.9 years) were used. Spectrophotometric and statistical research methods were used. A statistically significant decrease of superoxide dismutase, glutathione-S-transferase, glutathione-peroxidase, ceruloplasmin, an increase in the values of diene conjugates, malondialdehyde in the group of patients with OJNMG relative to the control was revealed, regardless of the level of bilirubin in the blood. The presence of malignant genesis of the disease with more intense changes in the studied parameters relative to control is accompanied. Comparison of indicators between groups of patients with OJ of different genesis showed a decrease in the values of glutathione-S-transferase and an increase in the level of diene conjugates in patients with OJMG and the level of bilirubin less than 60 µmol / L, as well as an increase in the content of diene conjugates in patients with OJNMG and a level of bilirubin 60- 200 µmol / L in comparison with the corresponding groups of patients with OJNMG. Thus, both in the groups with OJNMG and in the groups with OJMG, there is a significant decrease in the activity of the main antioxidant enzymes and an increase in lipid peroxidation products, regardless of the level of bilirubin in the blood. The presence of malignant genesis is characterized by more intense differences. The revealed changes can serve as additional criteria for optimizing the diagnosis and treatment of this cohort of patients.

LncRNA DPP10-AS1 promotes malignant processes through epigenetically activating its cognate gene DPP10 and predicts poor prognosis in lung cancer patients.

OBJECTIVE: The purpose of this study was to explore the function and gene expression regulation of the newly identified lncRNA DPP10-AS1 in lung cancer, and its potential value as a prognostic biomarker. METHODS: qRT-PCR and Western blot were conducted to detect the expression of DDP10-AS1 and DPP10 in lung cancer cell lines and tissues. The effects of DDP10-AS1 on DPP10 expression, cell growth, invasion, apoptosis, and in vivo tumor growth were investigated in lung cancer cells by Western blot, rescue experiments, colony formation, flow cytometry, and xenograft animal experiments. RESULTS: The novel antisense lncRNA DPP10-AS1 was found to be highly expressed in cancer tissues (P < 0.0001), and its upregulation predicted poor prognosis in patients with lung cancer (P = 0.0025). Notably, DPP10-AS1 promoted lung cancer cell growth, colony formation, and cell cycle progression, and repressed apoptosis in lung cancer cells by upregulating DPP10 expression. Additionally, DPP10-AS1 facilitated lung tumor growth via upregulation of DPP10 protein in a xenograft mouse model. Importantly, DPP10-AS1 positively regulated DPP10 gene expression, and both were coordinately upregulated in lung cancer tissues. Mechanically, DPP10-AS1 was found to associate with DPP10 mRNA but did not enhance DPP10 mRNA stability. Hypomethylation of DPP10-AS1 and DPP10 contributed to their coordinate upregulation in lung cancer. CONCLUSIONS: These findings indicated that the upregulation of the antisense lncRNA DPP10-AS1 promotes lung cancer malignant processes and facilitates tumorigenesis by epigenetically regulating its cognate sense gene DPP10. DPP10-AS1 may serve as a candidate prognostic biomarker and a potential therapeutic target in lung cancer.

Immunotherapeutic approaches of IL-1 neutralization in the tumor microenvironment.

IL-1 is a pleiotropic cytokine that controls inflammation, immunity, and hemopoiesis. The major IL-1 agonistic molecules are IL-1α and IL-1ß, which bind to IL-1R type I (IL-1R1) and induce similar biologic functions. The IL-1R antagonist (IL-1Ra) is a physiologic inhibitor of IL-1R1 signaling. In the tumor microenvironment, IL-1 is expressed by malignant, stromal, and infiltrating cells and supports tumor invasiveness and progression. We have shown that in the tumor microenvironment, the IL-1 agonistic molecules act different as a result of their local amounts and their compartmentalization within the producing cells. IL-1ß is produced mainly by myeloid cells upon inflammatory stimulation and is active as a mature, secreted molecule. The precursor of IL-1α (ProIL-1α) is biologically active; it is constitutively expressed in diverse tissue cells in basal levels, and its expression increases during stress or inflammation. ProIL-1α is mainly located in the cytosol or it is membrane associated. ProIL-1α also translocates into the nucleus and binds to chromatin. ProIL-1α is rarely actively secreted but is released from necrotizing tissues and serves as "alarmin" for initiation of inflammation. In the tumor microenvironment, IL-1ß promotes tumorigenesis, tumor invasiveness, and immunosuppression. On the other hand, membrane-associated forms of IL-1α support the development of anti-tumor immunity. In cancer patients, both IL-1 agonistic molecules coexist and interact with each other. Here, we discuss the role of IL-1 agonistic molecules in tumor progression and their potential to serve as targets in anti-tumor immunotherapeutic approaches. Our notion on the optimal conditions for IL-1 manipulation is also discussed.

Targeting the Tumor Microenvironment by Intervention in Interleukin-1 Biology.

The importance of anti-tumor immunity in the outcome of cancer is now unequivocally established and recent achivements in the field have stimulated the development of new immunotherapeutical approaches. In invasive tumors, widespread inflammation promotes invasiveness and concomitantly also inhibits anti-tumor immune responses. We suggest that efficient tumor treatment should target both the malignant cells and the tumor microenvironment. Interleukin-1 (IL-1) is a pro-inflammatory as well as an immunostimulatory cytokine that is abundant in the tumor microenvironment. Manipulation of IL-1 can thus serve as an immunotherapeutical approach to reduce inflammation/immunosuppression and thus enhance anti-tumor immunity. The two major IL-1 agonistic molecules are IL-1α and IL-1ß, which bind to the same IL-1 signaling receptor and induce the same array of biological activities. The IL-1 receptor antagonist (IL-Ra) is a physiological inhibitor of IL-1 that binds to its receptor without transmition of activation signals and thus serves as a decoy target. We have demonstrated that IL-1α and IL-1ß are different in terms of the producing cells and their compartmentalization and the amount. IL-1α is mainly expressed intracellularly, in the cytosol, in the nucleus or exposed on the cell membrane, however, it is rarely secreted. IL-1ß is active only as a secreted molecule that is mainly produced by activated myeloid cells. We have shown different functions of IL-1α and IL-1ß in the malignant process. Thus, in its membrane- associated form, IL-1α is mainly immunostimulatory, while IL-1ß that is secreted into the tumor microenvironment is mainly pro-inflammatory and promotes tumorigenesis, tumor invasiveness and immunosuppression. These distinct functions of the IL-1 agonistic molecules are mainly manifested in early stages of tumor development and the patterns of their expression dictate the direction of the malignant process. Here, we suggest that IL-1 modulation can serve as an effective mean to tilt the balance between inflammation and immunity in tumor sites, towards the latter. Different agents that neutralize IL-1, mainly the IL-Ra and specific antibodies, exist. They are safe and FDA-approved. The IL-1Ra has been widely and successfully used in patients with Rheumatoid arthritis, autoinflammatory diseases and various other diseases that have an inflammatory component. Here, we provide the rationale and experimental evidence for the use of anti-IL-1 agents in cancer patients, following first line therapy to debulk the major tumor's mass. The considerations and constraints of using anti-IL-1 treatments in cancer are also discussed. We hope that this review will stimulate studies that will fasten the application of IL-1 neutralization at the bedside of cancer patients.