MiRNA Expression in Neuroendocrine Neoplasms of Frequent Localizations

Neuroendocrine neoplasms (NEN) are infrequent malignant tumors of a neuroendocrine nature that arise in various organs. They occur most frequently in the lungs, intestines, stomach and pancreas. Molecular diagnostics and prognosis of NEN development are highly relevant. The role of clinical biomarkers can be played by microRNAs (miRNAs). This work is devoted to the analysis of data on miRNA expression in NENs. For the first time, a search for specificity or a community of their functional characteristics in different types of NEN was carried out. Their properties as biomarkers were also analyzed. To date, more than 100 miRNAs have been characterized as differentially expressed and significant for the development of NEN tumors. Only about 10% of the studied miRNAs are expressed in several types of NEN; differential expression of the remaining 90% was found only in tumors of specific localizations. A significant number of miRNAs have been identified as potential biomarkers. However, only a few miRNAs have values that characterized their quality as markers. The analysis demonstrates the predominant specific expression of miRNA in each studied type of NEN. This indicates that miRNA’s functional features are predominantly influenced by the tissue in which they are formed

The Features of Checkpoint Receptor—Ligand Interaction in Cancer and the Therapeutic Effectiveness of Their Inhibition

To date, certain problems have been identified in cancer immunotherapy using the inhibition of immune checkpoints (ICs). Despite the excellent effect of cancer therapy in some cases when blocking the PD-L1 (programmed death-ligand 1) ligand and the immune cell receptors PD-1 (programmed cell death protein 1) and CTLA4 (cytotoxic T-lymphocyte-associated protein 4) with antibodies, the proportion of patients responding to such therapy is still far from desirable. This situation has stimulated the exploration of additional receptors and ligands as targets for immunotherapy. In our article, based on the analysis of the available data, the TIM-3 (T-cell immunoglobulin and mucin domain-3), LAG-3 (lymphocyte-activation gene 3), TIGIT (T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains), VISTA (V-domain Ig suppressor of T-cell activation), and BTLA (B- and T-lymphocyte attenuator) receptors and their ligands are comprehensively considered. Data on the relationship between receptor expression and the clinical characteristics of tumors are presented and are analyzed together with the results of preclinical and clinical studies on the therapeutic efficacy of their blocking. Such a comprehensive analysis makes it possible to assess the prospects of receptors of this series as targets for anticancer therapy. The expression of the LAG-3 receptor shows the most unambiguous relationship with the clinical characteristics of cancer. Its inhibition is the most effective of the analyzed series in terms of the antitumor response. The expression of TIGIT and BTLA correlates well with clinical characteristics and demonstrates antitumor efficacy in preclinical and clinical studies, which indicates their high promise as targets for anticancer therapy. At the same time, the relationship of VISTA and TIM-3 expression with the clinical characteristics of the tumor is contradictory, and the results on the antitumor effectiveness of their inhibition are inconsistent

The Genes—Candidates for Prognostic Markers of Metastasis by Expression Level in Clear Cell Renal Cell Cancer

The molecular prognostic markers of metastasis are important for personalized approaches to clear cell renal cell carcinoma (ccRCC) treatment but markers for practical use are still missing. To address this gap we studied the expression of ten genes—CA9, NDUFA4L2, VWF, IGFBP3, BHLHE41, EGLN3, SAA1, CSF1R, C1QA, and FN1—through RT-PCR, in 56 ccRCC patients without metastases and with metastases. All of these, excluding CSF1R, showed differential and increased (besides SAA1) expression in non-metastasis tumors. The gene expression levels in metastasis tumors were decreased, besides CSF1R, FN1 (not changed), and SAA1 (increased). There were significant associations of the differentially expressed genes with ccRCC metastasis by ROC analysis and the Fisher exact test. The association of the NDUFA4L2, VWF, EGLN3, SAA1, and C1QA expression with ccRCC metastasis is shown for the first time. The CA9, NDUFA4L2, BHLHE4, and EGLN3 were distinguished as the strongest candidates for ccRCC metastasis biomarkers. We used an approach that presupposed that the metastasis marker was the expression levels of any three genes from the selected panel and received sensitivity (88%) and specificity (73%) levels with a relative risk of RR > 3. In conclusion, a panel of selected genes—the candidates in biomarkers of ccRCC metastasis—was created for the first time. The results might shed some light on the ccRCC metastasis processes

The Correlation of Ten Immune Checkpoint Gene Expressions and Their Association with Gastric Cancer Development

In the immunotherapy based on immune checkpoint inhibition (IC), additional ICs are being studied to increase its effectiveness. An almost unstudied feature is the possible co-expression of ICs, which can determine the therapeutic efficacy of their inhibition. For the selection of promising ICs, information on the association of their expression with cancer development may be essential. We have obtained data on the expression correlation of ADAM17, PVR, TDO2, CD274, CD276, CEACAM1, IDO1, LGALS3, LGALS9, and HHLA2 genes in gastric cancer (GC). All but one, TDO2, have other IC genes with co-expression at some stage. At the metastatic stage, the expression of the IDO1 does not correlate with any other gene. The correlations are positive, but the expressions of the CD276 and CEACAM1 genes are negatively correlated. The expression of TDO2 and LGALS3 is associated with GC metastasis. The expression of TDO2 four-fold higher in metastatic tumors than in non-metastatic tumors, but LGALS3 was two-fold lower. The differentiation is associated with IDO1. The revealed features of TDO2, with a significant increase in expression at the metastatic stage and the absence of other IC genes with correlated expression indicates that the prospect of inhibiting TDO2 in metastatic GC. IDO1 may be considered for inhibition in low-differentiated tumors

Expression of Immune Checkpoints in Malignant Tumors: Therapy Targets and Biomarkers for the Gastric Cancer Prognosis

To increase the effectiveness of anticancer therapy based on immune checkpoint (IC) inhibition, some ICs are being investigated in addition to those used in clinic. We reviewed data on the relationship between PD-L1, B7-H3, B7-H4, IDO1, Galectin-3 and -9, CEACAM1, CD155, Siglec-15 and ADAM17 expression with cancer development in complex with the results of clinical trials on their inhibition. Increased expression of the most studied ICs—PD-L1, B7-H3, and B7-H4—is associated with poor survival; their inhibition is clinically significant. Expression of IDO1, CD155, and ADAM17 is also associated with poor survival, including gastric cancer (GC). The available data indicate that CD155 and ADAM17 are promising targets for immune therapy. However, the clinical trials of anti-IDO1 antibodies have been unsatisfactory. Expression of Galectin-3 and -9, CEACAM1 and Siglec-15 demonstrates a contradictory relationship with patient survival. The lack of satisfactory results of these IC inhibitor clinical trials additionally indicates the complex nature of their functioning. In conclusion, in many cases it is important to analyze the expression of other participants of the immune response besides target IC. The PD-L1, B7-H3, B7-H4, IDO1 and ADAM17 may be considered as candidates for prognosis markers for GC patient survival