Relationship between the Ubiquitin-Proteasome System and Autophagy in Colorectal Cancer Tissue.

BACKGROUND: Dysregulation of the autophagy process via ubiquitin is associated with the occurrence of a number of diseases, including cancer. The present study analyzed the changes in the transcriptional activity of autophagy-related genes and the ubiquitination process (UPS) in colorectal cancer tissue. (2) Methods: The process of measuring the transcriptional activity of autophagy-related genes was analyzed by comparing colorectal cancer samples from four clinical stages I-IV (CS I-IV) of adenocarcinoma to the control (C). The transcriptional activity of genes associated with the UPS pathway was determined via the microarray technique (HG-U133A, Affymetrix). (3) Results: Of the selected genes, only PTEN-induced kinase 1 (PINK1) indicated statistical significance for all groups of colon cancer tissue transcriptome compared to the control. The transcriptional activity of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene increased in all stages of the cancer, but the p-value was only less than 0.05 in CSIV vs. C. Forkhead box O1 (FOXO 1) and ubiquitin B (UBB) are statistically overexpressed in CSI. (4) Conclusions: The pathological expression changes in the studied proteins observed especially in the early stages of colorectal cancer suggest that the dysregulation of ubiquitination and autophagy processes occur during early neoplastic transformation. Stopping or slowing down the processes of removal of damaged proteins and their accumulation may contribute to tumor progression and poor prognosis.

Elranatamab: a new promising BispAb in multiple myeloma treatment.

INTRODUCTION: Multiple myeloma is a B-cell malignancy caused by proliferating plasma cells in the bone marrow microenvironment in collaboration with various cell lineage subsets and growth factors without any perfect regulation and tendency to clonal heterogeneity. Despite remarkable improvement in MM treatment and the overall survival of patients, multiple myeloma remains an incurable disease with the tendency to relapse. Therefore, there is an urgent need for new therapeutic options to provide a stabilized response to treatment with long-term duration. AREAS COVERED: Elranatamab (PF-06863135), is a novel heterodimeric humanized full-length bispecific IgG2 kappa antibody derived from 2 mAbs, the anti-BCMA mAb (PF-06863058) and the anti-CD3 mAb (PF-06863059), not yet licensed in routine use. This binding affinity of elranatamab to BCMA and CD3 has been optimized to potentially prompt more potent T cell-mediated anti-myeloma activity. Subcutaneous (s.c.) administration of elranatamab is superior in comparison to intravenous (i.v.), thus it is associated with lower incidence of adverse events, even in higher doses. EXPERT OPINION: Currently, elranatamab is being investigated in a few clinical studies, and the preliminary results are very encouraging. At the time of writing this review there were no full papers published and all of the data in the literature were based on abstract presentations which carry limitations.

Transcription of Autophagy Associated Gene Expression as Possible Predictors of a Colorectal Cancer Prognosis.

(1) Background: Autophagy plays a dual role in oncogenesis-it contributes to the growth of the tumor and can inhibit its development. The aim of this study was to assess changes in the transcriptional activity of LAMP-2, BECN1, PINK1, and FOXO1 genes involved in the autophagy process in histopathologically confirmed adenocarcinoma sections of colorectal cancer: (2) Methods: A gene expression profile analysis was performed using HG-U133A and the RT-qPCR reaction. The transcriptional activity of genes was compared in sections of colorectal cancer in the four clinical stages (CSI-CSIV) concerning the control group; (3) Results: In CSI, the transcriptional activity of the PINK1 gene is highest; in CS II, the LAMP-2 gene is highest, while FOXO1 increases gradually from CSI reaching a maximum in CSIII. There is no BECN1 gene expression in colorectal cancer cells; (4) Conclusions: The observed differences in the mRNA concentration profile of autophagy-related genes in colon cancer specimens may indicate the role of autophagy in the pathogenesis of this cancer. Genes involved in autophagy may be diagnostic tools for colorectal cancer screening and personalized therapy in the future.

The role of autophagy in acute myeloid leukemia development.

INTRODUCTION: Autophagy is a highly conservative self-degradative process. It aims at elimination-impaired proteins and cellular organelles. Previous research confirmed the autophagy role in cancer pathogenesis. AREAS COVERED: This article discusses the role of autophagy in the development of AML. Autophagy seems to be a 'double-sword' mechanism, hence, either its suppression or induction could promote neoplasm growth. This mechanism could also be the aim of the 'molecular targeted therapy.' Chemo- and radiotherapy induce cellular stress in neoplasm cells with subsequent autophagy suppression. Simultaneously, it is claimed that the autophagy suppression increases chemosensitivity 'in neoplastic cells. Some agents, like bortezomib, in turn could promote autophagy process, e.g. in AML (acute myeloid leukemia). However, currently there are not many studies focusing on the role of autophagy in patients suffering for AML. In this review, we summarize the research done so far on the role of autophagy in the development of AML. EXPERT OPINION: The analysis of autophagy genes expression profiling in AML could be a relevant factor in the diagnostic process and treatment 'individualization.' Autophagy modulation seems to be a relevant target in the oncological therapy - it could limit disease progression and increase the effectiveness of treatment.

Elotuzumab in the treatment of relapsed and refractory multiple myeloma.

Multiple myeloma (MM) is still considered an incurable disease. However, drugs with different mechanisms of action that can improve the efficiency of treatment offer hope. Still, there are concerns about an unacceptable increase in toxicity with such regimens. The results of recently published clinical studies of elotuzumab in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone confirm previous hopes to improve the effect of that treatment. Humanized monoclonal antibodies aimed at SLAMF7 stimulate natural killer cells to fight against MM cells. Elotuzumab used in combination with lenalidomide/dexamethasone or with pomalidomide/dexamethasone is approved by the US FDA to treat patients with relapsed and/or refractory MM. The article is a summary of the recent knowledge about the possibility of using elotuzumab in the treatment of relapsed and/or refractory MM and shows its potential uses in the future.

The Expression Patterns of BECN1, LAMP2, and PINK1 Genes in Colorectal Cancer Are Potentially Regulated by Micrornas and CpG Islands: An In Silico Study.

BACKGROUND: Autophagy plays a dual role of tumor suppression and tumor promotion in colorectal cancer. The study aimed to find those microRNAs (miRNAs) important in BECN1, LAMP2, and PINK1 regulation and to determine the possible role of the epigenetic changes in examined colorectal cancer using an in silico approach. METHODS: A total of 44 pairs of surgically removed tumors at clinical stages I‒IV and healthy samples (marginal tissues) from patients' guts were analyzed. Analysis of the obtained results was conducted using the PL-Grid Infrastructure and Statistica 12.0 program. The miRNAs and CpG islands were estimated using the microrna.org database and MethPrimer program. RESULTS: The autophagy-related genes were shown to be able to be regulated by miRNAs (BECN1-49 mRNA, LAMP2-62 mRNA, PINK1-6 mRNA). It was observed that promotion regions containing at least one CpG region were present in the sequence of each gene. CONCLUSIONS: The in silico analysis performed allowed us to determine the possible role of epigenetic mechanisms of regulation gene expression, which may be an interesting therapeutic target in the treatment of colorectal cancer.

Heat shock proteins as a new, promising target of multiple myeloma therapy.

Introduction: The results of therapy of the multiple myeloma (MM) patients remain unsatisfactory despite the constantly observed progress in treatment.Areas covered: It has been shown that mechanisms regulated by heat shock proteins (HSPs) play an important role in pathogenesis of MM and resistance developing to treatment, which constitute a protective shield against external damaging factors in healthy and cancerous cells.Expert opinion: Inhibiting these mechanisms seems to be the natural way of therapy in MM patients. In vitro studies have shown promising effects in the form of an increase in the apoptosis index of MM cells exposed to HSP inhibitors. The observations are very promising in the early stages of clinical trials with HSP inhibitors, such as tanespimycin, in the relapsed/refractory MM patients. Effects were more pronounced when combined with bortezomib. It seems that enriching the range of anti-myeloma drugs with HSP inhibitors may be the next step in the future of extending life of patients with multiple myeloma.

Genes involved in the regulation of different types of autophagy and their participation in cancer pathogenesis.

Autophagy is a highly conserved mechanism of self-digestion that removes damaged organelles and proteins from cells. Depending on the way the protein is delivered to the lysosome, four basic types of autophagy can be distinguished: macroautophagy, selective autophagy, chaperone-mediated autophagy and microautophagy. Macroautophagy involves formation of autophagosomes and is controlled by specific autophagy-related genes. The steps in macroautophagy are initiation, phagophore elongation, autophagosome maturation, autophagosome fusion with the lysosome, and proteolytic degradation of the contents. Selective autophagy is macroautophagy of a specific cellular component. This work focuses on mitophagy (selective autophagy of abnormal and damaged mitochondria), in which the main participating protein is PINK1 (phosphatase and tensin homolog-induced putative kinase 1). In chaperone-mediated autophagy, the substrate is bound to a heat shock protein 70 chaperone before it is delivered to the lysosome. The least characterized type of autophagy is microautophagy, which is the degradation of very small molecules without participation of an autophagosome. Autophagy can promote or inhibit tumor development, depending on the severity of the disease, the type of cancer, and the age of the patient. This paper describes the molecular basis of the different types of autophagy and their importance in cancer pathogenesis.

Profile of gene expression of TLR-signaling pathways in colorectal cancer tissues.

Toll-like receptors (TLRs) are involved in transduction of molecular signals in immune process such as induction and regulation of immunity, production of cytokines, and recognition of specific molecular patterns on the surface of microorganisms, but also in cancer development-which was partially proven in previous studies. There is a lack of detailed research on differentiating levels of TLR expression in colorectal cancer at different stages of its advancement, so in our study we want to determine whether there is such a difference of TLRs and TLR-connected protein expression. In this study, 83 samples of colorectal adenocarcinoma (varying clinical degrees) and 40 slices of healthy colon tissue have been analyzed. The delivered material was subjected to homogenization and extraction of total RNA. The isolated RNA was subsequently purified and valued quantitatively and qualitatively. Quantification was performed using a spectrophotometer GeneQuant II. The RNA concentration in the tested samples was determined spectrophotometrically. A qualitative assessment was performed by performing electrophoresis on a 1% agarose gel stained with ethidium bromide. The expression profile of the genes encoding the TLRs was determined using oligonucleotide microarray HG-U133A. To determine the mRNA (messenger RNA), differentiate cancerous tissue from normal colon using PL-Grid Infrastructure. The results were analyzed statistically, taking a significance level P < 0.05. In the study were found three proteins, DUSP2, IFNγ, EIF4A1, associated with TLR system, that differentiate early stages of colorectal cancer of healthy tissue, moreover eleven, inter alia: vascular endothelial growth factor (VEGF), which differentiate high stage of cancer of healthy tissues. The results emphasize the role of pathways associated with TLR activation in the pathogenesis of colorectal cancer. In summary, molecular studies on the development of colorectal cancer will enable the introduction of minimally invasive genetic diagnosis of early forms of cancer. In addition, identification of new signaling pathways can provide the basis for developing new therapeutic methods.

Expression of Migration-Related Genes in Human Colorectal Cancer and Activity of a Disintegrin and Metalloproteinase 17.

INTRODUCTION: The ability to form metastases which depends on the mechanisms of cell migration is an important element of the progression of cancer. In the present study we analyzed the genes involved in the regulation of migration in colon cancer cells. MATERIALS AND METHODS: A total of 20 pairs of surgically removed tumoral and healthy (marginal) tissues samples from colorectal cancer patients at clinical stages I-II and III-IV were analyzed. The isolation of RNA from CRC and normal tissues and its subsequent molecular analysis were performed according to manufacturer's instructions. Microarray data analysis was performed using the GeneSpring 11.5 platform and Significance Analysis of Microarrays (SAM). In SAM analysis to identify significantly differentially expressed genes score and q-value parameters were used. RESULTS: The largest increase in expression of genes was shown by MMP9, ADAM17, EphA2, and TIMP. CONCLUSIONS: Presented genes, especially ADAM17, MMP9, EphA2, TIMP1, ICAM 11, and CD4, may be used as prognostic markers of advanced stages of colorectal cancer, contributing to the development of new lines of therapy focused on reducing metastasis of the primary tumor.