The Regulatory Role of Pivotal MicroRNAs in the AKT Signaling Pathway in Breast Cancer.

Breast cancer is the most prevalent type of cancer among women, and it remains the main challenge despite improved treatments. MicroRNAs (miRNAs) are a small non-coding family of RNAs that play an indispensable role in regulating major physiological processes, including differentiation, proliferation, invasion, migration, cell cycle regulation, stem cell maintenance apoptosis, and organ development. The dysregulation of these tiny molecules is associated with various human malignancies. More than 50% of these non-coding RNA sequences estimated have been placed on genomic regions or fragile sites linked to cancer. Following the discovery of the first signatures of specific miRNA in breast cancer, numerous researches focused on involving these tiny RNAs in breast cancer physiopathology as a new therapeutic approach or as reliable prognostic biomarkers. In the current review, we focus on recent findings related to the involvement of miRNAs in breast cancer via the AKT signaling pathway related to their clinical implications.

Cancer immunotherapy: Challenges and limitations.

Although cancer immunotherapy has taken center stage in mainstream oncology inducing complete and long-lasting tumor regression, only a subset of patients receiving treatment respond and others relapse after an initial response. Different tumor types respond differently, and even in cancer types that respond (hot tumors), we still observe tumors that are unresponsive (cold tumors), suggesting the presence of resistance. Hence, the development of intrinsic or acquired resistance is a big challenge for the cancer immunotherapy field. Resistance to immunotherapy, including checkpoint inhibitors, CAR-T cell therapy, oncolytic viruses, and recombinant cytokines arises due to cancer cells employing several mechanisms to evade immunosurveillance.

From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy.

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

Melatonin increases the anticancer potential of doxorubicin in Caco-2 colorectal cancer cells.

Colorectal cancer (CC) is an important human malignancy with high cancer related death worldwide. The chemotherapy using doxorubicin hydrochloride is one of the most common cancer therapeutic methods. However, drug resistance lowers the treatment efficacy in CC patients. The combination therapies seem to be more promising by taking the advantage of synergistic effects. The present study aimed to evaluate a new strategy to enhance the anticancer activity of doxorubicin in Caco-2 CC cell line by co-administration of melatonin. The effects of doxorubicin, melatonin, and their combinations (Dox-Mel) were investigated on the proliferation and viability, morphological alterations, and tumor spheroid formation. Flow cytometry was employed to compare the apoptotic situation of the cells in study groups. Changes in metastatic potential of the cells were assessed by wound healing assay and trans-well migration assays. Moreover, expression of BAX, SMAC, BCL-2, SURVIVIN, MMP-2, and MMP-9 genes were evaluated by quantitative real time PCR and western blotting. Our study showed that doxorubicin, melatonin, and Dox-Mel significantly decreased the proliferation and viability, tumor spheroid formation, invasion, and migration. Furthermore, the changes were in a concentration and time dependent manner. There was an increase in apoptosis rate in the treatment groups. Expression of genes involved in apoptosis and cell motility were altered significantly. It was observed that anticancer activity of Dox-Mel combination was significantly more than doxorubicin and melatonin treatments alone. We showed an enhanced apoptotic and anticancer activity of doxorubicin and melatonin combination chemotherapy on CC cell line than doxorubicin or melatonin treatments alone. This combination could promote the treatment efficiency and alleviate the un-intended side effects by lowering the dose of doxorubicin prescription.

The role of tumor suppressor short non-coding RNAs on breast cancer.

Characterized by remarkable levels of aggression and malignancy, BC remains one of the leading causes of death in females world wide. Accordingly, significant efforts have been made to develop early diagnostic tools, increase treatment efficacy, and improve patient prognosis. Hopefully, many of the molecular mechanisms underlying BC have been detected and show promising targeting potential. In particular, short and long non-coding RNAs (ncRNAs) are a class of endogenous BC controllers and include a number of different species including microRNAs, Piwi-interacting RNAs, small nucleolar RNA, short interfering RNAs, and tRNA-derivatives. In this review, we discuss the tumor suppressing roles of ncRNAs in the context of BC, and the mechanisms by which ncRNAs target tumor hallmarks, including apoptosis, proliferation, invasion, metastasis, epithelial-mesenchymal transition, angiogenesis, and cell cycle progression, in addition to their diagnostic and prognostic significance in cancer treatment.

The pivotal role of MicroRNAs in glucose metabolism in cancer.

Cancer cells are able to undergo aerobic glycolysis and metabolize glucose to lactate instead of oxidative phosphorylation, which is known as Warburg effect. Accumulating evidence has revealed that microRNAs regulate cancer cell metabolism, which manifest a higher rate of glucose metabolism. Various signaling pathways along with glycolytic enzymes are responsible for the emergence of glycolytic dependence. MicroRNAs are a class of non-coding RNAs that are not translated into proteins but regulate target gene expression or in other words function pre-translationally and post-transcriptionally. MicroRNAs have been shown to be involved in various biological processes, including glucose metabolism via targeting major transcription factors, enzymes, oncogenes or tumor suppressors alongside the oncogenic signaling pathways. In this review, we describe the regulatory role of microRNAs of cancer cell glucose metabolism, including in the glucose uptake, glycolysis, tricarboxylic acid cycle and several signaling pathways and further suggest that microRNA-based therapeutics can be used to inhibit the process of glucose metabolism reprogramming in cancer cells and thus suppressing cancer progression.

Resistance mechanisms to immune checkpoints blockade by monoclonal antibody drugs in cancer immunotherapy: Focus on myeloma.

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the accumulation of neoplastic proliferation of a plasma cell in the bone marrow that produces a monoclonal immunoglobulin. The immune checkpoint inhibitors against programmed death-1/programmed death-1 ligand and cytotoxic T-lymphocyte antigen 4 axis have demonstrated appropriate anticancer activity in several solid tumors and liquid cancers, and are rapidly transforming the practice of medical oncology. However, in a high percentage of patients, the efficacy of immune checkpoints blockade remains limited due to innate or primary resistance. Moreover, the malignancies progress in many patients due to acquired or secondary resistance, even after the clinical response to immune checkpoints' blockade. The evidence shows that multiple tumor-intrinsic and tumor-extrinsic factors and alterations in signaling pathways are involved in primary and secondary resistance to immune checkpoints blockade. Improved identification of intrinsic and extrinsic factors and mechanisms of resistance or response to immune checkpoints blockade may not only provide novel prognostic or predictive biomarkers but also guide the optimal combination/sequencing of immune checkpoint blockade therapy in the clinic. Here, we review the underlying biology and role of immune checkpoints blockade in patients with MM. Furthermore, we review the host and tumor-related factor effects on immune checkpoints blockade in MM immunotherapy.

Mechanisms of Dysregulated Humoral and Cellular Immunity by SARS-CoV-2.

The current coronavirus disease 2019 (COVID-19) pandemic, a disease caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), was first identified in December 2019 in China, and has led to thousands of mortalities globally each day. While the innate immune response serves as the first line of defense, viral clearance requires activation of adaptive immunity, which employs B and T cells to provide sanitizing immunity. SARS-CoV-2 has a potent arsenal of mechanisms used to counter this adaptive immune response through processes, such as T cells depletion and T cell exhaustion. These phenomena are most often observed in severe SARS-CoV-2 patients, pointing towards a link between T cell function and disease severity. Moreover, neutralizing antibody titers and memory B cell responses may be short lived in many SARS-CoV-2 patients, potentially exposing these patients to re-infection. In this review, we discuss our current understanding of B and T cells immune responses and activity in SARS-CoV-2 pathogenesis.

Regulatory role of microRNAs in cancer through Hippo signaling pathway.

Cancer is the major cause of death worldwide in countries of all income levels. The Hippo signaling pathway is a Drosophila kinase gene that was identified to regulate organ size, cell regeneration, and contribute to tumorigenesis. A huge variety of extrinsic and intrinsic signals regulate the Hippo signaling pathway. The Hippo signaling pathway consists of a wide array of components that merge numerous signals such as mechanical signals to address apoptosis resistance, cell proliferation, cellular outputs of growth, cell death and survival at cellular and tissue level. Recent studies have shed new light on the regulatory role of microRNAs in Hippo signaling and how they contribute to cancer progression. MicroRNAs influence various cancer-related processes such as, apoptosis, proliferation, migration, cell cycle and metabolism. Inhibition and overexpression of miRNAs via miRNA mimics and miRNA inhibitors, respectively, can uncover a hopeful and reliable insight for treatment and early diagnosis of cancer patients. In this review we will discuss our current understanding of regulatory role of miRNAs in Hippo signaling pathway.

Covid-19: Perspectives on Innate Immune Evasion.

The ongoing outbreak of Coronavirus disease 2019 infection achieved pandemic status on March 11, 2020. As of September 8, 2020 it has caused over 890,000 mortalities world-wide. Coronaviral infections are enabled by potent immunoevasory mechanisms that target multiple aspects of innate immunity, with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) able to induce a cytokine storm, impair interferon responses, and suppress antigen presentation on both MHC class I and class II. Understanding the immune responses to SARS-CoV-2 and its immunoevasion approaches will improve our understanding of pathogenesis, virus clearance, and contribute toward vaccine and immunotherepeutic design and evaluation. This review discusses the known host innate immune response and immune evasion mechanisms driving SARS-CoV-2 infection and pathophysiology.

First Serological & Molecular Study of Coxiella burnetii in Stray, Domestic Cats, and Their Owners in Iran.

Coxiella burnetii, the agent of Q fever, is recognized as a worldwide zoonosis a wide host and potentially complex reservoir systems. Infected ruminants are the main source of infection for humans, but cats also represent a potential source of infection. The prevalence of C burnetii in cats in Iran is unknown and the risks of transmission to humans are undetermined. This study aimed to determine the prevalence of C burnetii in domestic cats and their owners. An Enzyme-linked immunosorbent assay was used for detection of anti-C burnetii antibodies in both cats and humans. Cats serum samples and humans serum samples (n = 85) were tested with indirect ELISA. C burnetii was diagnosed using real time- polymerase chain reaction. Antibodies were detected in 19 sera of 85 (22.35%) samples in stray cats, 9 sera of 78 (11.53%) samples of domestic cats and 4 sera of 78 (5.12%) samples of their owners. This first study of C burnetii prevalence in cats in Iran has indicated that positive samples can be found throughout the country and these results confirm that Iranian cats have been exposed to C burnetii. Moreover, this study demonstrates that cat owners, breeders and veterinary personnel might be at higher risk of exposure of C burnetii.

Vascular mimicry: changing the therapeutic paradigms in cancer.

Cancer is a major problem in the health system, and despite many efforts to effectively treat it, none has yet been fully successful. Angiogenesis and metastasis are considered as major challenges in the treatment of various cancers. Researchers have struggled to succeed with anti-angiogenesis drugs for the effective treatment of cancer, although new challenges have emerged in the treatment with the emergence of resistance to anti-angiogenesis and anti-metastatic drugs. Numerous studies have shown that different cancers can resist anti-angiogenesis drugs in a new process called vascular mimicry (VM). The studies have revealed that cells resistant to anti-angiogenesis cancer therapies are more capable of forming VMs in the in vivo and in vitro environment, although there is a link between the presence of VM and poor clinical outcomes. Given the importance of the VM in the challenges facing cancer treatment, researchers are trying to identify factors that prevent the formation of these structures. In this review article, it is attempted to provide a comprehensive overview of the molecules and main signaling pathways involved in VM phenomena, as well as the agents currently being identified as anti-VM and the role of VM in response to treatment and prognosis of cancer patients.

Targeting cancer stem cells by melatonin: Effective therapy for cancer treatment.

Melatonin is a physiological hormone produced by the pineal gland. In recent decades, enormous investigations showed that melatonin can prompt apoptosis in cancer cells and inhibit tumor metastasis and angiogenesis in variety of malignancies such as ovarian, melanoma, colon, and breast cancer; therefore, its possible therapeutic usage in cancer treatment was confirmed. CSCs, which has received much attention from researchers in past decades, are major challenges in the treatment of cancer. Because CSCs are resistant to chemotherapeutic drugs and cause recurrence of cancer and also have the ability to be regenerated; they can cause serious problems in the treatment of various cancers. For these reasons, the researchers are trying to find a solution to destroy these cells within the tumor mass. In recent years, the effect of melatonin on CSCs has been investigated in some cancers. Given the importance of CSCs in the process of cancer treatment, this article reviewed the studies conducted on the effect of melatonin on CSCs as a solution to the problems caused by CSCs in the treatment of various cancers.

The apatinib inhibits breast cancer cell line MDA-MB-231 in vitro by inducing apoptosis, cell cycle arrest, and regulating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways.

BACKGROUND AND PURPOSE: Breast cancer is one of the most common cancers and leading causes of death in the women worldwide. The evidence shows efficacy of apatinib against breast cancer. Accordingly, the present study was conducted to investigate the effect of apatinib on apoptosis, cell cycle, and Mitogen­Activated Protein Kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways in the breast cancer MDA-MB-231 cell line. METHODS: The effects of apatinib on viability, morphology, tumor spheroid, cell cycle, migration, invasion, and apoptosis of MDA-MB-231 breast cancer cells were evaluated in vitro. In addition, expression of proteins involved in NF-κB and MAPK signaling pathways was evaluated using the western blotting analysis. RESULTS: Apatinib decreased viability, tumor spheroid, migration, and invasion of MDA-MB-231 cells. Furthermore, apatinib altered morphology and regulated cell cycle which followed by apoptosis induction in MDA-MB-231 cells. Apatinib decreased expression of p-p65 and p65 proteins in NF-κB signaling pathways and increased expression of p38, p-p38, JNK, and p-JNK in MAPK signaling pathways. CONCLUSION: The results suggested that apatinib can inhibit proliferation, migration and invasion of breast cancer cell line MDA-MB-231 through inducing apoptosis, cell cycle arrest, and regulating NF-κB and MAPK signaling pathways.

Promising approaches in cancer immunotherapy.

Immunotherapy is a promising field, which enhances and harnesses the powers of the host immune system against cancer and in recent years, has become a major application of the fundamental research of cancer immunology. Cancer immunotherapy is often more targeted than non-specific therapy approaches, including radiotherapy or chemotherapy, as the immune system can be trained to remember cancer cells, highlighting a durable approach that can be maintained after the treatment completion. Immunotherapy functions by directing the immune system to attack the tumour cells via targeting tumour antigens, also enhancing the existing anti-tumour immune responses. Current strategies include non-specific immunotherapy, cancer vaccines, oncolytic virus therapy, monoclonal antibodies, immune checkpoints and T cell therapy. The combination of effective approaches can increase the immunotherapy efficacy, leading to durable anti-tumour immune responses. This review will discuss the immunotherapy approaches, particularly immune checkpoints and T cell therapy, which are the most common clinical applications in cancer immunotherapy.

Association of rs1946518 C/A Polymorphism in Promoter Region of Interleukin 18 Gene and Breast Cancer Risk in Iranian Women: A Case-control Study.

Breast cancer (BC) is the most frequently diagnosed cancer among women in the world. Genetic polymorphisms in Interleukin (IL) genes are one of the most important risk factors in BC. The aim of this study was to investigate the association of rs1946518 C/A polymorphism in the promoter region of the IL-18 gene and BC risk in Iranian women. In this case-control study, we recruited 140 women with BC as a case group and 140 age and ethnically matched women as healthy controls from East Azerbaijan, Tabriz in Iran. The genomic DNA was extracted using a salting-out method from peripheral blood leukocytes. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The genotype distribution in BC patients was 37.86% CC, 47.14% CA, and 15.00% AA, whereas in healthy controls these were 40.72% CC, 42.85% CA, and 16.43% AA. Statistical analysis showed that the genotype and allele frequencies of IL-18 rs1946518 C/A polymorphism were not significantly different between BC patients and healthy controls (p>0.05). The only significant difference between cases and controls was related to family history (p=0.023). In conclusion, our study indicated that IL-18 rs1946518 C/A polymorphism was not associated with BC in the Iranian women population. However, more studies on different races and geographic areas are required to determine the exact role of rs1946518 C/A polymorphism in prognosis, diagnosis, and risk of BC.

Association of IL-10, IL-18, and IL-33 genetic polymorphisms with recurrent pregnancy loss risk in Iranian women.

Recurrent pregnancy loss (RPL) is a heterogeneous disease with three or more consecutive abortions before 20 weeks of pregnancy. Recently, inflammatory factors such as interleukins (IL) have been found to be a significant factor in the RPL. The objective of this study was to investigate the association between RPL and IL-10 (rs1800896), IL-18 (rs1946518) and IL-33 (rs1929992) genes polymorphisms in Iranian women. The study participants consisted of 300 women with RPL and the control group comprised of 300 healthy women with successful delivery. Genomic DNA was extracted from peripheral blood, and genotyping was performed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). There were no significant differences in the frequencies of genotype and allele in IL-10 gene polymorphism (rs1800896) between patients and control group (p > .005). In contrast, there were significant differences in the frequencies of CC genotype in IL-18 gene polymorphism (rs1946518) between patients and the control groups (p = .004; OR =0.990; 95% CI: 0.320-8.855). Also, there were significant differences in the frequencies of GA genotype in IL-33 gene polymorphism (rs1929992) between patients and the control groups (p = .001; OR =0.955; 95% CI: 0.239-9.807). Present study showed that the rs1800896 polymorphism (IL-10) might not play role in RPL in the Iranian population; whereas rs1946518 (IL-18) and rs1929992 (IL-33) polymorphisms may be associated with the risk of RPL in the Iranian women.

In vivo and in vitro impact of miR-31 and miR-143 on the suppression of metastasis and invasion in breast cancer.

PURPOSE: The microRNA (miR)-31 and miR-143 are pleiotropic anti-metastatic miRs, with an expression that decreases significantly in metastatic breast cancer cells. The aim of this study was to investigate the effect of miR-31 and miR-143 inhibition on metastasis and invasion in both MDA-MB231, MDA-MB468 as well as the MCF-7 breast cancer cell lines and 5-week old female mice. METHODS: Following the cloning of miR-31 and miR-143 into vectors, their expressions were determined before treatment with constructs of miR-31 and miR-143 in cancer cell lines and normal breast cells. Then miR-31 and miR-143 were transfected to the cell lines and the expression was assessed after 48 hrs. Moreover, the levels of migration and invasion were determined in cell lines. These experiments were performed in 5-week old female mice. RESULTS: The results showed that miR-31 expression before the transfection of miR-31 construct was decreased 4, 70 and 100 times in MCF-7, MDA-MB468 and MDA-MB231 cell lines, respectively, in comparison to normal breast cells; but after the transfection of miR-31 construct, the expression of miR-31 increased 80 times. Additionally, invasion and migration decreased by 15 and 10 times in MDAMB-468. All of the modifications in miR-143 were low in comparison to miR-31. The results of the in vivo experiments were approximately the same as in the in vitro experiments. CONCLUSIONS: It appears that the use of miR-31 is highly efficient than miR-143 in the inhibition of invasion and metastasis in breast cancer. Our study improved our conception about miR-31 and miR-143 and their roles in the identification and therapy of breast cancer.

Reciprocal role of hBD2 and hBD3 on the adaptive immune response by measuring T lymphocyte proliferation in terms of CD4 and CCR6 expression.

Background Human ß-defensins (hBD2 and hBD3) are small cationic antimicrobial peptides of innate immune system which can act as a barrier against the majority of pathogens, contributing to the host immune defence. Objective The aim of study is to determine whether hBD2 and hBD3 play a role in development and proliferation of human effector CD4 T cells or not. Furthermore, if enhanced proliferation is observed in the presence of hBD2 and hBD3, these data will demonstrate whether chemokine receptor type 6 (CCR6) is required to be present for this activity to occur. Methods In this study, we examined the effect of hBD2 and hBD3 on CD4+ T cell proliferation in CCR6+ and CCR6- T cells through co-culture of peripheral blood mononuclear cells with anti-CD3 and anti-CD28 stimulation in the presence or absence of hBD2 and hBD3. Proliferation was assessed using flow cytometry. Results It was demonstrated that, co-culture with hBD2 and hBD3 led to up-regulation of CD4+ T cell proliferation after 72 h whereas, CD4+ T cell proliferation was suppressed after 96 h. On the other hand, CCR6- and CCR6+ T cell proliferation was up-regulated after 72 h. But, CCR6+ only was down-regulated in the second cycle in the presence of hBD3. In contrast, after 96 h CCR6+ and CCR6- T cell proliferation was decreased. Conclusion Collectively, our data indicated that hBD2 and hBD3 play a positive and negative regulatory role in development and proliferation of human effector CD4+ T cells which is essential for optimal adaptive immune responses and the control of immunopathology.

Early growth response 2 and Egr3 are unique regulators in immune system.

The immune system is evolved to defend the body against pathogens and is composed of thousands of complicated and intertwined pathways, which are highly controlled by processes such as transcription and repression of cellular genes. Sometimes the immune system malfunctions and a break down in self-tolerance occurs. This lead to the inability to distinguish between self and non-self and cause attacks on host tissues, a condition also known as autoimmunity, which can result in chronic debilitating diseases. Early growth response genes are family of transcription factors comprising of four members, Egr1, Egr2, Egr3 and Egr4. All of which contain three cyc2-His2 zinc fingers. Initially, Egr2 function was identified in the regulation of peripheral nerve myelination, hindbrain segmentation. Egr3, on the other hand, is highly expressed in muscle spindle development. Egr2 and Egr3 are induced due to the antigen stimulation and this signaling is implemented through the B and T cell receptors in the adaptive immunity. T cell receptor signaling plays a key role in Egr 2 and 3 expressions via their interaction with NFAT molecules. Egr 2 and 3 play a crucial role in regulation of the immune system and their involvement in B and T cell activation, anergy induction and preventing the autoimmune disease has been investigated. The deficiency of these transcription factors has been associated to deficient Cbl-b expression, a resistant to anergy phenotype, and expression of effector and activated T cells.