USP11 promotes prostate cancer progression by up-regulating AR and c-Myc activity.

Androgen receptor (AR) is a main driver for castration-resistant prostate cancer (CRPC). c-Myc is an oncogene underlying prostate tumorigenesis. Here, we find that the deubiquitinase USP11 targets both AR and c-Myc in prostate cancer (PCa). USP11 expression was up-regulated in metastatic PCa and CRPC. USP11 knockdown (KD) significantly inhibited PCa cell growth. Our RNA-seq studies revealed AR and c-Myc as the top transcription factors altered after USP11 KD. ChIP-seq analysis showed that either USP11 KD or replacement of endogenous USP11 with a catalytic-inactive USP11 mutant significantly decreased chromatin binding by AR and c-Myc. We find that USP11 employs two mechanisms to up-regulate AR and c-Myc levels: namely, deubiquitination of AR and c-Myc proteins to increase their stability and deubiquitination of H2A-K119Ub, a repressive histone mark, on promoters of AR and c-Myc genes to increase their transcription. AR and c-Myc reexpression in USP11-KD PCa cells partly rescued cell growth defects. Thus, our studies reveal a tumor-promoting role for USP11 in aggressive PCa through upregulation of AR and c-Myc activities and support USP11 as a potential target against PCa.

SMAD3 promotes expression and activity of the androgen receptor in prostate cancer.

Overexpression of androgen receptor (AR) is the primary cause of castration-resistant prostate cancer, although mechanisms upregulating AR transcription in this context are not well understood. Our RNA-seq studies revealed that SMAD3 knockdown decreased levels of AR and AR target genes, whereas SMAD4 or SMAD2 knockdown had little or no effect. ChIP-seq analysis showed that SMAD3 knockdown decreased global binding of AR to chromatin. Mechanistically, we show that SMAD3 binds to intron 3 of the AR gene to promote AR expression. Targeting these binding sites by CRISPRi reduced transcript levels of AR and AR targets. In addition, ∼50% of AR and SMAD3 ChIP-seq peaks overlapped, and SMAD3 may also cooperate with or co-activate AR for AR target expression. Functionally, AR re-expression in SMAD3-knockdown cells partially rescued AR target expression and cell growth defects. The SMAD3 peak in AR intron 3 overlapped with H3K27ac ChIP-seq and ATAC-seq peaks in datasets of prostate cancer. AR and SMAD3 mRNAs were upregulated in datasets of metastatic prostate cancer and CRPC compared with primary prostate cancer. A SMAD3 PROTAC inhibitor reduced levels of AR, AR-V7 and AR targets in prostate cancer cells. This study suggests that SMAD3 could be targeted to inhibit AR in prostate cancer.

Adipose lipolysis is important for ethanol to induce fatty liver in the National Institute on Alcohol Abuse and Alcoholism murine model of chronic and binge ethanol feeding.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) pathologies include steatosis, inflammation, and injury, which may progress to fibrosis, cirrhosis, and cancer. The liver receives ~60% of fatty acids from adipose tissue triglyceride hydrolysis, but the role of this lipolytic pathway in ALD development has not been directly examined in any genetic animal models with selective inactivation of adipose lipolysis. APPROACH AND RESULTS: Using adipose-specific comparative gene identification-58 (CGI-58) knockout (FAT-KO) mice, a model of impaired adipose lipolysis, we show that mice deficient in adipose lipolysis are almost completely protected against ethanol-induced hepatic steatosis and lipid peroxidation when subjected to the National Institute on Alcohol Abuse and Alcoholism chronic and binge ethanol feeding model. This is unlikely due to reduced lipid synthesis because this regimen of ethanol feeding down-regulated hepatic expression of lipogenic genes similarly in both genotypes. In the pair-fed group, FAT-KO relative to control mice displayed increased hepatocyte injury, neutrophil infiltration, and activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the liver; and none of these were exacerbated by ethanol feeding. Activation of STAT3 is associated with a marked increase in hepatic leptin receptor mRNA expression and adipose inflammatory cell infiltration. CONCLUSIONS: Our findings establish a critical role of adipose lipolysis in driving hepatic steatosis and oxidative stress during ALD development.

The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways.

Acute myeloid leukemia (AML) comprises a multifarious and heterogeneous array of illnesses characterized by the anomalous proliferation of myeloid cells in the bone marrow microenvironment (BMM). The BMM plays a pivotal role in promoting AML progression, angiogenesis, and metastasis. The immune checkpoints (ICs) and metabolic processes are the key players in this process. In this review, we delineate the metabolic and immune checkpoint characteristics of the AML BMM, with a focus on the roles of BMM cells e.g. tumor-associated macrophages, natural killer cells, dendritic cells, metabolic profiles and related signaling pathways. We also discuss the signaling pathways stimulated in AML cells by BMM factors that lead to AML progression. We then delve into the roles of immune checkpoints in AML angiogenesis, metastasis, and cell proliferation, including co-stimulatory and inhibitory ICs. Lastly, we discuss the potential therapeutic approaches and future directions for AML treatment, emphasizing the potential of targeting metabolic and immune checkpoints in AML BMM as prognostic and therapeutic targets. In conclusion, the modulation of these processes through the use of directed drugs opens up new promising avenues in combating AML. Thereby, a comprehensive elucidation of the significance of these AML BMM cells' metabolic and immune checkpoints and signaling pathways on leukemic cells can be undertaken in the future investigations. Additionally, these checkpoints and cells should be considered plausible multi-targeted therapies for AML in combination with other conventional treatments in AML. Video Abstract.

Histone demethylase JMJD1A in cancer progression and therapeutic resistance.

JMJD1A (also called lysine demethylase 3A [KDM3A]) belongs to the Jumonji C family of histone demethylases. It specifically removes the repressive mono- or di-methyl marks from histone H3 at lysine 9 and thus contributes to the activation of gene transcription. JMJD1A plays a key role in a variety of biological processes such as spermatogenesis, metabolism, sex determination, and stem cell activity. JMJD1A is upregulated in various types of cancers and can promote cancer development, progression, and therapeutic resistance. JMJD1A can epigenetically regulate the expression or activity of transcription factors such as c-Myc, androgen receptor (AR), estrogen receptor (ER), ß-catenin, and so on. Expression and activity of JMJD1A in cancer cells can be regulated at transcriptional, post-transcriptional, and post-translational levels. Targeting JMJD1A may repress the oncogenic transcription factors as a potential anticancer therapy.

The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: inflammasome and JaK inhibitors as potential promising therapies.

The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and finding a safe therapeutic strategy and effective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinflammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest inflammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases.

Concomitant overexpression of mir-182-5p and mir-182-3p raises the possibility of IL-17-producing Treg formation in breast cancer by targeting CD3d, ITK, FOXO1, and NFATs: A meta-analysis and experimental study.

T cells are polarized toward regulatory T cells (Tregs) in tumor microenvironment by the shuttling of microRNAs that target T cell-activating signaling pathways. We evaluated the expression of the miR-182 cluster (miR-96, 182, and 183) in peripheral blood mononuclear cells (PBMCs) of patients with breast cancer (BC), and T cell polarization by the expression of FOXO1, NFATs, ITK, TCR/CD3 complex, and IL-2/IL-2RA. Twenty-six microRNAs overexpressed in tumor tissues and sera of these patients were extracted by a meta-analysis. Then, the expression of the miR-182 cluster was investigated in PBMCs and sera of these patients and correlated with their targets in PBMCs. Finally, miR-182 was cloned into Jurkat cells to evaluate its effects on T cell polarization. FOXO1, CD3d, ITK, NFATc3, NFATc4, and IL-2RA were targeted by miR-182, due to which their expression decreased in PBMCs of patients. Although IL-6, IL-17, and TGF-ß increased after miR-182 transduction, IL-2 dramatically decreased. We revealed CD4+ FOXP3+ T cell differentiation in the miR-182-transduced group. Although miR-182 has inhibitory effects on T cells by the inhibition of FOXO1, TCR/CD3 complex, NFATs, and IL-2/IL-2RA signaling pathways, it increases FOXP3, TGF-ß, and IL-17 expression to possibly drive T cell deviation toward the transitional state of IL-17-producing Tregs and Treg formation in the end.

CML derived exosomes promote tumor favorable functional performance in T cells.

BACKGROUND: Leukemic cells facilitate the creation of the tumor-favorable microenvironment in the bone marrow niche using their secreted factors. There are not comprehensive details about immunosuppressive properties of chronic myelogenous leukemia-derived exosomes in the bone marrow stromal and immune compartment. We explained here that K562-derived exosomes could affect the gene expression, cytokine secretion, nitric oxide (NO) production, and redox potential of human primary cord blood-derived T cells (CB T cells). METHODS: Human primary cord blood-derived T cells were treated with K562-derived exosomes. We evaluated the expression variation of some critical genes activated in suppressor T cells. The alterations of some inflammatory and anti-inflammatory cytokines levels were assessed using ELISA assay and real-time PCR. Finally, NO production and intracellular ROS level in CB T cells were evaluated using Greiss assay and flow cytometry, respectively. RESULTS: Our results showed the over-expression of the genes involved in inhibitory T cells, including NQO1, PD1, and FoxP3. In contrast, genes involved in T cell activation such as CD3d and NFATc3 have been reduced significantly. Also, the expression of interleukin 10 (IL-10) and interleukin 6 (IL-6) mRNAs were significantly up-regulated in these cells upon exosome treatment. In addition, secretion of the interleukin 10, interleukin 6, and interleukin 17 (IL-17) proteins increased in T cells exposed to K562-derived exosomes. Finally, K562-derived exosomes induce significant changes in the NO production and intracellular ROS levels in CB T cells. CONCLUSIONS: These results demonstrate that K562-derived exosomes stimulate the immunosuppressive properties in CB-derived T cells by inducing anti-inflammatory cytokines such as IL-10, reducting ROS levels, and arising of NO synthesis in these cells. Moreover, considering the elevation of FOXP3, IL-6, and IL-17 levels in these cells, exosomes secreted by CML cells may induce the fates of T cells toward tumor favorable T cells instead of conventional activated T cells.

Investigation of combined photodynamic and radiotherapy effects of gallium phthalocyanine chloride on MCF-7 breast cancer cells.

In this study, we evaluated the effect of gallium phthalocyanine chloride (GaPcCl) as a radio- and photosensitizer on MCF-7 breast cancer cell line. We incubated cells with GaPcCl in different concentrations (from 3.125 to 100 µg/ml). Then cells in separate groups were exposed to different light doses (1.8 and 2.8 J/cm2) at wavelength of 660 nm and 2-Gy X-ray ionizing radiation, alone and in combination. Finally, cell survival and apoptosis were determined by MTT assay and flow cytometry, respectively. The results showed that the deactivated GaPcCl at concentration of 100 µg/ml reduces the cell viability up to 15%. While, photoactivated GaPcCl (100 µg/ml) at light dose of 2.8 J/cm2 significantly decreases cell viability up to 55.3%. Although MTT assay demonstrated that GaPcCl is not act as a radiosensitizer, flow cytometry showed significant increase in cell apoptosis when GaPcCl was exposed to 2 Gy X-ray. Using of GaPcCl-PDT (photodynamic therapy) integration with X-ray substantially increased cell death in comparison to the absence of X-ray. Furthermore, flow cytometry displayed a significant increase in apoptosis cells (especially late apoptosis) in this combination therapy. Our result proved that GaPcCl is an effective photosensitizer in MCF-7 human breast cancer cell line. The combination of GaPcCl-PDT and radiotherapy can be an efficient treatment against cancer. This approach needs further investigations on animal models for human purposes.Graphic abstract.

JAK Inhibition as a New Treatment Strategy for Patients with COVID-19.

After the advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the outbreak of coronavirus disease 2019 (COVID-19) commenced across the world. Understanding the Immunopathogenesis of COVID-19 is essential for interrupting viral infectivity and preventing aberrant immune responses before a vaccine can be developed. In this review, we provide the latest insights into the roles of angiotensin-converting enzyme II (ACE2) and Ang II receptor-1 (AT1-R) in this disease. Novel therapeutic strategies, including recombinant ACE2, ACE inhibitors, AT1-R blockers, and Ang 1-7 peptides, may prevent or reduce viruses-induced pulmonary, cardiac, and renal injuries. However, more studies are needed to clarify the efficacy of these therapeutics. Furthermore, considering the common role of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in AT1-R expressed on peripheral tissues and cytokine receptors on the surface of immune cells, potential targeting of this pathway using JAK inhibitors (JAKinibs) is suggested as a promising approach in patients with COVID-19 who are admitted to hospitals. In addition to antiviral therapy, potential ACE2- and AT1-R-inhibiting strategies, and other supportive care, we suggest other potential JAKinibs and novel anti-inflammatory combination therapies that affect the JAK-STAT pathway in patients with COVID-19. Since the combination of MTX and baricitinib leads to outstanding clinical outcomes, the addition of baricitinib to MTX might be a potential strategy.

Alteration of cellular and immune-related properties of bone marrow mesenchymal stem cells and macrophages by K562 chronic myeloid leukemia cell derived exosomes.

Leukemic cells can impact the bone marrow niche to create a tumor-favorable microenvironment using their secreted factors. Little knowledge is available about immunosuppressive and tumor-promoting properties of chronic myeloid leukemia derived exosomes in bone marrow stromal components. We report here that K562-derived exosomes can affect the gene expression, cytokine secretion, nitric oxide (NO) production, and redox potential of bone marrow mesenchymal stem cells (BM-MSCs) and macrophages. Human BM-MSCs and mouse macrophages were treated with K562-derived exosomes. Our results demonstrated that the expression of the genes involved in hematopoietic developmental pathways and immune responses, including C-X-C motif chemokine 12 (Cxcl12), Dickkopf-related protein 1 (DKK1), wnt5a, interleukin 6 (IL-6), transforming growth factor-beta, and tumor necrosis factor-alpha (TNF-alpha), changed with respect to time and exosome concentration in BM-MSCs. The TNF-alpha level was higher in exosome-treated BM-MSCs compared with the control. Exosome treatment of BM-MSCs led to an increased production of NO and a decreased production of reactive oxygen species (ROS) in a time- and concentration-dependent manner. We have shown that K562-derived exosomes induce overexpression of IL-10 and TNF-alpha and downregulation of iNOS transcript levels in macrophages. The enzyme-linked immunosorbent assay results showed that TNF-alpha and IL-10 secretions increased in macrophages. Treatment of macrophages with purified exosomes led to reduced NO and ROS levels. These results suggest that K562-derived exosomes may alter the local bone marrow niche toward a leukemia-reinforcing microenvironment. They can modulate the inflammatory molecules (TNF-alpha and NO) and the redox potential of BM-MSCs and macrophages and direct the polarization of macrophages toward tumor-associated macrophages.

Sub-lethal antimicrobial photodynamic inactivation: an in vitro study on quorum sensing-controlled gene expression of Pseudomonas aeruginosa biofilm formation.

During antimicrobial photodynamic inactivation (APDI) in the treatment of an infection, it is likely that microorganisms would be exposed to sub-lethal doses of APDI (sAPDI). Although sAPDI cannot kill microorganisms, it can significantly affect microbial virulence. In this study, we evaluated the effect of sAPDI using methylene blue (MB) on the expression of genes belonging to two quorum sensing (QS) operons (rhl and las systems) and two genes necessary for biofilm formation (pelF and pslA) under QS control in Pseudomonas aeruginosa. Biofilm formation ability of P. aeruginosa ATCC 27853 exposed to sAPDI (MB at 0.012 mM and light dose of 23 J/cm2) was evaluated using triphenyl tetrazolium chloride (TTC) assay and scanning electron microscopy (SEM). The effect of sAPDI on expression of rhlI, rhlR, lasI, lasR, pelF, and pslA were also evaluated by quantitative real-time polymerase chain reaction. Quantitative assay (TTC) results and morphological observations (SEM) indicated that a single sAPDI treatment resulted in a significant decrease in biofilm formation ability of P. aeruginosa ATCC 27853 compared to their non-treated controls (P = 0.012). These results were consistent with the expression of genes belonging to rhl and las systems and pelF and pslA genes. The results suggested that the transcriptional decreases caused by MB-sAPDI did lead to phenotypic changes.

The diversity in the expression profile of caveolin II transcripts, considering its new transcript in breast cancer.

Most studies have revealed the effects of caveolins in cancer inhibition. However, due to a lack of reports about their new transcripts, their presence and their effects on different cancers are unclear. This study was conducted to evaluate the cavolin-2 (cav-2) transcripts expression changes in tumoral and corresponding tissues and in contralateral breast, to investigate their variation associated with the variation of caveolin-1 (cav-1) expression in breast cancer. There were 40 breast-derived tumoral, corresponding, and contralateral tissues obtained from the patients with breast cancer. The RNA and proteins were extracted from these samples. So, cav-1 and cav-2 transcripts' variation were assessed in whole tumoral, corresponding, and contralateral breast. Also, their expression modifications were evaluated via the Western blotting technique. The results derived from this study verified the presence of transcript III of cav-2 for the first time, which was reported only in the gene bank, but we could not detect and validate any protein associated with these transcripts. Also, the decreasing trend of cav-1 and the cav-2 (transcripts I and II) were observed in tumoral tissues compared to unaffected tissues especially in stages I and II. It seems that the descending expression levels of cav-1 and cav-2 (transcript I, II) besides the lasting expression of cav-2 (transcript III) are associated with the incidence and promotion of breast cancer, especially in the initial stages of breast cancer. So, this may show a potential in determining the patients who can undergo the prophylactic mastectomy. Moreover, the results of the study demonstrated that transcript III may be a candidate as a non-coding RNA.

Novel Epigenetic Controlling of Hypoxia Pathway Related to Overexpression and Promoter Hypomethylation of TET1 and TET2 in RPE Cells.

CpG methylation of DNA takes part in a specific epigenetic memory that plays crucial roles in the differentiation and abnormality of the cells. The methylation pattern aberration of genomes is affected in three ways, namely DNA methyltransferase (DNMT), ten-eleven translocation (TET), and methyl-binding domain (MBD) proteins. Of these, TET enzymes have recently been demonstrated to be master modifier enzymes in the DNA methylation process. Additionally, recent studies emphasize that not only epigenetic phenomena play a role in controlling hypoxia pathway, but the hypoxia condition also triggers hypomethylation of genomes that may help with the expression of hypoxia pathway genes. In this study, we suggested that TET1 and TET2 could play a role in the demethylation of genomes under chemical hypoxia conditions. Herein, the evaluating methylation status and mRNA expression of mentioned genes were utilized through real-time PCR and methylation-specific PCR (MSP), respectively. Our results showed that TET1 and TET2 genes were overexpressed (P < 0.05) under chemical hypoxia conditions in Retinal Pigment Epithelial (RPE) cells, whereas the promoter methylation status of them were hypomethylated in the same condition. Therefore, chemical hypoxia not only causes overexpression of TET1 and TET2 but also could gradually do promoter demethylation of same genes. This is the first study to show the relationship between epigenetics and the expression of mentioned genes related to hypoxia pathways. Furthermore, it seems that these associations in RPE cells are subjected to chemical hypoxia as a mechanism that could play a crucial role in methylation pattern changes of hypoxia-related diseases such as cancer and ischemia. J. Cell. Biochem. 118: 3193-3204, 2017. © 2017 Wiley Periodicals, Inc.

Connection between MiR-490 and CCND1 and GSK3ß genes play an effective role in Wnt signaling pathway in colorectal cancer.

The Wnt signaling pathway is identified as one of the main disrupted pathways in Colorectal cancer (CRC). Results from studies focusing on this route will aid greatly in the detection and treatment of CRC. MicroRNAs (MiRs), particularly MiR-490, has emerged as key regulator of gene expression in biological pathways, making it an attractive research target. This is notably true for the Wnt signaling pathway, which is usually disordered in CRC tissues. This study aimed to evaluate the expression level of MiR-490 isomiRs and determine some of its key target genes involved in Wnt signaling pathway in CRC tissues and cell lines, based on experimental and bioinformatics analysis. Elevated expression of GSK3ß and CCND1 indicate that the progression of CRC tumor is associated with the inhibitory effect of MiR-490 isomiRs on the Wnt/ß-catenin signaling pathway. This finding was supported by the observation of a positive connection between the expression pattern of miR-490-3p and 5p, and CCND1 and GSK3ß in CRC. The valuable results of this study provide a means of identifying biomarkers with the potential to either inhibit or activate CRC cellular pathways.

Breast cancer tumor microenvironment affects Treg/IL-17-producing Treg/Th17 cell axis: Molecular and therapeutic perspectives.

The tumor microenvironment (TME) comprises a variety of immune cells, among which T cells exert a prominent axial role in tumor development or anti-tumor responses in patients with breast cancer (BC). High or low levels of anti-inflammatory cytokines, such as transforming growth factor ß, in the absence or presence of proinflammatory cytokines, such as interleukin-6 (IL-6), delineate the fate of T cells toward either regulatory T (Treg) or T helper 17 (Th17) cells, respectively. The transitional state of RORγt+Foxp3+ Treg (IL-17-producing Treg) resides in the middle of this reciprocal polarization, which is known as Treg/IL-17-producing Treg/Th17 cell axis. TME secretome, including microRNAs, cytokines, and extracellular vesicles, can significantly affect this axis. Furthermore, immune checkpoint inhibitors may be used to reconstruct immune cells; however, some of these novel therapies may favor tumor development. Therefore, understanding secretory and cell-associated factors involved in their differentiation or polarization and functions may be targeted for BC management. This review discusses microRNAs, cytokines, and extracellular vesicles (as secretome), as well as transcription factors and immune checkpoints (as cell-associated factors), which influence the Treg/IL-17-producing Treg/Th17 cell axis in BC. Furthermore, approved or ongoing clinical trials related to the modulation of this axis in the TME of BC are described to broaden new horizons of promising therapeutic approaches.

Overexpression of miR-490-5p/miR-490-3p Potentially Induces IL-17-Producing T Cells in Patients With Breast Cancer.

Objective: Breast cancer (BC) is the most prevalent female cancer globally and this is also true in Iranian women. Alteration in circulating microRNAs affects the fate of immune cells, affecting immunological response to neoplasia. Materials and Methods: We investigated the expression of miR-490-5p and miR-490-3p in peripheral blood mononuclear cells (PBMCs) and plasma of patients with BC. Moreover, the correlation of these microRNAs with the expression levels of CD3d, interleukin 2 (IL-2), IL-2 receptor chain alpha (IL-2RA), forkhead box O1 (FOXO1) and nuclear factor of activated T cells 5 (NFAT5) were investigated. Results: Two groups, including 42 patients with BC, aged 22-75 years with stage I, II, III disease without administration of immunosuppressive chemotherapy regimens/radiotherapy and 40 healthy controls aged 27-70 years, participated. Overexpression and higher circulation levels of miR-490-5p and miR-490-3p were found in the patients with consequent down-regulation of all targets investigated in PBMCs. Furthermore, there was a significant negative correlation between the overexpression of these microRNAs and a reduction in levels of CD3d, IL-2, and IL-2RA in patients with BC. Conclusion: These results suggest that down-regulation of the target genes by miR-490 may predispose and facilitate the production of Th17 lymphocytes and IL-17-producing Tregs. The variation in miR-490-5p/-3p and the investigated targets in the PBMCs of BC patients may be used as non-invasive diagnostic markers.

miR-1290 contributes to oncogenesis and angiogenesis via targeting of THBS1, DKK3 and, SCAI.

Introduction: Colorectal cancer (CRC) is the third most common cancer in the world with high mortality, hence, understanding the molecular mechanisms involved in the tumor progression are important for CRC diagnosis and treatment. MicroRNAs (miRNAs) are key gene expression regulators that can function as tumor suppressors or oncogenes in tumor cells, and modulate angiogenesis as a critical process in tumor metastasis. MiR-1290 has been demonstrated as an onco-miRNA in various types of cancer, however, the role of miR-1290 in CRC is not fully understood. This study aimed to investigate the oncogenic and angiogenic potential of miR-1290 in CRC. Methods: Lenti-miR-1290 was transduced into HCT116, SW480, and human umbilical vein endothelial cells (HUVECs). By bioinformatics analysis, we identified thrombospondin 1 (THBS1) as a novel predicted target for miR-1290. Quantitative real-time PCR, western blotting, and luciferase reporter assay were used to demonstrate suppression of miR-1290 target genes including THBS1, Dickkopf Wnt signaling pathway inhibitor 3 (DKK3), and suppressor of cancer cell invasion (SCAI) in HCT116 and HUVECs. Cell cycle analysis, proliferation, migration and, tube formation were determined by flow cytometry, MTT, wound healing, and tube formation assays, respectively. Results: MiR-1290 significantly decreased the expression of THBS1, DKK3, and SCAI. We demonstrated that miR-1290 enhanced proliferation, migration, and angiogenesis partially through suppression of THBS1, DKK3, and SCAI in CRC. Conclusion: These results suggest a novel function of miR-1290 which may contribute to tumorigenesis and angiogenesis in CRC.

A success targeted nano delivery to lung cancer cells with multi-walled carbon nanotubes conjugated to bromocriptine.

In this research, a new nano drug-based multi-walled carbon nanotubes (MWCNTs) was prepared and evaluated qualitatively. Bromocriptine (BRC) was conjugated to functionalized carbon nanotubes. Then, the CHNS, FT-IR, SEM, and RAMAN tests for characterization of the conjugated drug were done. The nanofluid-containing nano-drug was evaluated on lung cancer cells (A549 & QU-DB) and MRC5 by MTT and flow cytometry tests. Then, the gene expression studies of dopamine receptor genes were done before and after nano-drug treatment. After that, a western blotting test was carried out for further investigation of dopamine receptors protein production. Finally, Bax and Bcl-2 secretion were measured by the ELISA method in cells affected by MWCNTs-BRC Nf compared to untreated cells. The results showed that the nano-drug had a significant lethal effect on cancer cells, while it had no toxicity on MRC5. Also, the nano-drug could significantly induce apoptosis in lung cancer cells at a lower dose compared to the drug alone. In this study, a targeted nano-drug delivery system was designed, and its performance was evaluated based on neurotransmitter pathways, and the results showed that it may be useful in the treatment of lung cancer. However, additional studies on animal models are underway.