Targeting Nanog expression increased Cisplatin chemosensitivity and inhibited cell migration in Gastric cancer cells.

Regardless of significant advances in cancer treatment, gastric cancer (GC) incidence rate is increasing worldwide. As one of the main transcription factors participating in stemness, Nanog plays a pivotal role in various aspects of tumorigenesis, metastasis, and chemosensitivity. Given that, the current research intended to evaluate the potential effects of Nanog suppression on the GC cell Cisplatin chemosensitivity and in vitro tumorigenesis. First, bioinformatics analysis was performed to evaluate the effect of Nanog expression on GC patients' survival. The MKN-45 human GC cells were transfected with specific siRNA targeting Nanog and/or treated with Cisplatin. Then, to study cellular viability and apoptosis, MTT assay and Annexin V/PI staining were done, respectively. Also, the scratch assay was performed to investigate cell migration, and MKN-45 cell stemness was followed using colony formation assay. Western blotting and qRT-PCR were used for gene expression analysis. The findings demonstrated that Nanog overexpression was significantly correlated with poor survival of GC patients, and siRNA-mediated Nanog silencing strongly increased MKN-45 cell sensitivity to Cisplatin through apoptosis induction. Also, Nanog suppression combined with Cisplatin resulted in the upregulation of the Caspase-3 and Bax/Bcl-2 ratio at mRNA levels and increased Caspase-3 activation. Moreover, reduced expression of Nanog, separately or combined with Cisplatin, inhibited MKN-45 cell migration by downregulating MMP2 mRNA and protein expression levels. The results also evidenced CD44 and SOX-2 downregulation aligned with a decreased rate of MKN-45 cell colony formation ability through treatments. Besides, Nanog downregulation significantly decreased MDR-1 mRNA expression. Taken together, the results of this study indicated that Nanog could be suggested as a promising target combined with Cisplatin-based GC therapies for reducing drug side effects and improving patients' outcomes.

Dendritic cell-derived exosomes: A new horizon in personalized cancer immunotherapy?

Dendritic cells (DCs) release nanometer-sized membrane vesicles known as dexosomes, containing different molecules, particularly proteins, for presenting antigens, i.e., major histocompatibility complex (MHC)-I/II and CD86. Dexosomes can, directly and indirectly, stimulate antigen-reactive CD8+ and CD4+ T cell responses. Antigen-loaded dexosomes can lead to the development of potent anti-tumoral immune responses. Notably, developing dexosome-based cell-free vaccines could serve as a new vaccination platform in the era of immunotherapy for various cancers. Furthermore, combining dexosomes vaccination strategies with other treatment approaches can considerably increase tumor-specific T cell responses. Herein, we aimed to review how dexosomes interact with immune cells, e.g., CD4+ and CD8+ T cells and natural killer (NK) cells. Besides, we discussed the limitations of this approach and suggested potential strategies to improve its effectiveness for affected patients.

Nanog suppression enhanced the chemosensitivity of human non-small-cell lung cancer cells to Cisplatin and inhibited cell migration.

Lung cancer is the leading cause of cancer-associated death in the world. As one of the leading transcription factors in controlling stemness features, Nanog was shown to promote cancer progression, metastasis, and drug resistance. Considering that, this research was conducted to evaluate the effect of Nanog suppression using specific siRNA on the chemosensitivity of lung cancer cells to Cisplatin through inhibition of cell proliferation, migration, and stemness as well as apoptosis induction. Then, A549 lung cancer cells were transfected with Nanog siRNA and treated with Cisplatin individually or combined. Subsequently, to investigate cell proliferation and apoptosis induction, MTT assay and Annexin V/PI staining were performed, respectively. Also, colony formation assay was carried out to evaluate cell stemness features, and migration ability of A549 cells was followed using a wound-healing assay. Gene expression was quantified via qRT-PCR. The obtained results illustrated that siRNA-mediated Nanog suppression remarkably increased the chemosensitivity of A549 cells to Cisplatin through apoptosis induction. Consistently, Nanog suppression combined with Cisplatin led to upregulation of Caspase-3 apoptotic gene and Bax/Bcl-2 ratio. Besides, Nanog knockdown, individually or combined with Cisplatin, prevented colony formation ability of A549 cells by downregulating Sox2 and CD44 genes. It was also indicated that the combination therapy remarkably downregulated MMP9 expression and subsequently suppressed A549 cell migration. A significant reduction was also observed in c-Myc and PD-L1 gene expression levels. In conclusion, the findings of the current study demonstrated that silencing Nanog combined with Cisplatin could be a potent treatment approach for lung cancer patients.

Nanog, as a key cancer stem cell marker in tumor progression.

Cancer stem cells (CSCs) are a small population of malignant cells that induce tumor onset and development. CSCs share similar features with normal stem cells in the case of self-renewal and differentiation. They also contribute to chemoresistance and metastasis of cancer cells, leading to therapeutic failure. To identify CSCs, multiple cell surface markers have been characterized, including Nanog, which is found at high levels in different cancers. Recent studies have revealed that Nanog upregulation has a substantial association with the advanced stages and poor prognosis of malignancies, playing a pivotal role through tumorigenesis of multiple human cancers, including leukemia, liver, colorectal, prostate, ovarian, lung, head and neck, brain, pancreatic, gastric and breast cancers. Nanog through different signaling pathways, like JAK/STAT and Wnt/ß-catenin pathways, induces stemness, self-renewal, metastasis, invasiveness, and chemoresistance of cancer cells. Some of these signaling pathways are common in various types of cancers, but some have been found in one or two cancers. Therefore, this review aimed to focus on the function of Nanog in multiple cancers based on recent studies surveying the suitable approaches to target Nanog and inhibit CSCs residing in tumors to gain favorable results from cancer treatments.

siRNA-mediated silencing of Nanog reduces stemness properties and increases the sensitivity of HepG2 cells to cisplatin.

Liver cancer is one of the most lethal cancers having worldwide prevalence. Despite significant progress in cancer therapy, liver cancer-induced mortality is very high. Nanog, as an essential transcription factor modulating cellular multipotency, causes tumor progression, drug resistance, and preserves stemness properties in various tumors such as liver cancer. Thus, this research was conducted to evaluate the impact of combination therapy of Nanog siRNA/cisplatin on the sensitivity of liver cancer cells to this drug. HepG2 cells were transfected with Nanog siRNA and treated with cisplatin, individually and in combination. Then, it was observed that in transfected HepG2 cells, Nanog expression was significantly reduced at mRNA level and also these cells were sensitized to cisplatin. In addition, to assess the impact of Nanog siRNA and cisplatin individually and in combination on cells' viability, migration capacity, apoptosis, and cell cycle progression, the MTT, wound healing, colony formation assay, Annexin V/PI staining, and flow cytometry assays were applied on HepG2 cells, respectively. Also, the quantitive Real-Time PCR was used to check the expression of stemness-associated genes (CD44, CD133, and Sox2), and apoptosis-related genes (caspase-3, 8, 9, BAX and Bcl2) after combination therapy. It is indicated that the combination of Nanog siRNA and cisplatin significantly reduced proliferation, migration, and colony formation ability, as well as increased apoptosis rate, and cell cycle arrest. Also, it is found that the combination of Nanog siRNA and cisplatin down-regulated the expression of stemness-associated genes and up-regulated apoptosis-related genes in HepG2 cells. Hence, it can be suggested that Nanog inhibition in combination with cisplatin is a potential therapeutic strategy for developing new therapeutic approaches for liver cancer.

Tumor necrosis factor­α in systemic lupus erythematosus: Structure, function and therapeutic implications (Review).

Tumor necrosis factor­α (TNF­α) is a pleiotropic pro­inflammatory cytokine that contributes to the pathophysiology of several autoimmune diseases, such as multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis and systemic lupus erythematosus (SLE). The specific role of TNF­α in autoimmunity is not yet fully understood however, partially, in a complex disease such as SLE. Through the engagement of the TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), both the two variants, soluble and transmembrane TNF­α, can exert multiple biological effects according to different settings. They can either function as immune regulators, impacting B­, T­ and dendritic cell activity, modulating the autoimmune response, or as pro­inflammatory mediators, regulating the induction and maintenance of inflammatory processes in SLE. The present study reviews the dual role of TNF­α, focusing on the different effects that TNF­α may have on the pathogenesis of SLE. In addition, the efficacy and safety of anti­TNF­α therapies in preclinical and clinical trials SLE are discussed.

The importance of immune checkpoints in immune monitoring: A future paradigm shift in the treatment of cancer.

The growth and development of cancer are directly correlated to the suppression of the immune system. A major breakthrough in cancer immunotherapy depends on various mechanisms to detect immunosuppressive factors that inhibit anti-tumor immune responses. Immune checkpoints are expressed on many immune cells such as T-cells, regulatory B cells (Bregs), dendritic cells (DCs), natural killer cells (NKs), regulatory T (Tregs), M2-type macrophages, and myeloid-derived suppressor cells (MDSCs). Immune inhibitory molecules, including CTLA-4, TIM-3, TIGIT, PD-1, and LAG-3, normally inhibit immune responses via negatively regulating immune cell signaling pathways to prevent immune injury. However, the up-regulation of inhibitory immune checkpoints during tumor progression on immune cells suppresses anti-tumor immune responses and promotes immune escape in cancer. It has recently been indicated that cancer cells can up-regulate various pathways of the immune checkpoints. Therefore, targeting immune inhibitory molecules through antibodies or miRNAs is a promising therapeutic strategy and shows favorable results. Immune checkpoint inhibitors (ICIs) are introduced as a new immunotherapy strategy that enhance immune cell-induced antitumor responses in many patients. In this review, we highlighted the function of each immune checkpoint on different immune cells and therapeutic strategies aimed at using monoclonal antibodies and miRNAs against inhibitory receptors. We also discussed current challenges and future strategies for maximizing these FDA-approved immunosuppressants' effectiveness and clinical success in cancer treatment.

The roles of signaling pathways in SARS-CoV-2 infection; lessons learned from SARS-CoV and MERS-CoV.

The number of descriptions of emerging viruses has grown at an unprecedented rate since the beginning of the 21st century. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is the third highly pathogenic coronavirus that has introduced itself into the human population in the current era, after SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Molecular and cellular studies of the pathogenesis of this novel coronavirus are still in the early stages of research; however, based on similarities of SARS-CoV-2 to other coronaviruses, it can be hypothesized that the NF-κB, cytokine regulation, ERK, and TNF-α signaling pathways are the likely causes of inflammation at the onset of COVID-19. Several drugs have been prescribed and used to alleviate the adverse effects of these inflammatory cellular signaling pathways, and these might be beneficial for developing novel therapeutic modalities against COVID-19. In this review, we briefly summarize alterations of cellular signaling pathways that are associated with coronavirus infection, particularly SARS-CoV and MERS-CoV, and tabulate the therapeutic agents that are currently approved for treating other human diseases.

The oncogenic potential of NANOG: An important cancer induction mediator.

Cancer stem cells (CSCs) are a unique population in the tumor, but they only comprise 2%-5% of the tumor bulk. Although CSCs share several features with embryonic stem cells, CSCs can give rise to the tumor cells. CSCs overexpress embryonic transcription factor NANOG, which is downregulated in differentiated tissues. This transcription factor confers CSC's stemness, unlimited self-renewal, metastasis, invasiveness, angiogenesis, and drug-resistance with the assistance of WNT, OCT4, SOX2, Hedgehog, BMI-1, and other complexes. NANOG facilitates CSCs development via multiple pathways, like angiogenesis and lessening E-cadherin expression levels, which paves the road for metastasis. Moreover, NANOG represses apoptosis and leads to drug-resistance. This review aims to highlight the pivotal role of NANOG and the pertained pathways in CSCs. Also, this current study intends to demonstrate that targeting NANOG can dimmish the CSCs, sensitize the tumor to chemotherapy, and eradicate the cancer cells.

Signaling pathways and microRNAs, the orchestrators of NANOG activity during cancer induction.

Cancer stem cells (CSCs) are a small part of cancer cells inside the tumor that have similar characteristics to normal stem cells. CSCs stimulate tumor initiation and progression in a variety of cancers. Several transcription factors such as NANOG, SOX2, and OCT4 maintain the characteristics of CSCs and their upregulation is seen in many malignancies resulting in increased metastasis, invasion, and recurrence. Among these factors, NANOG plays an important role in regulating the self-renewal and pluripotency of CSCs and the clinical significance of NANOG has been suggested as a marker of CSCs in many cancers. The up and down-regulation of NANOG is associated with several important signaling pathways, including JAK/STAT, Wnt/ß-catenin, Notch, TGF-ß, Hedgehog, and several microRNAs (miRNAs). In this review, we will investigate the function of NANOG in CSCs and the molecular mechanism of its regulation by signaling pathways and miRNAs. We will also investigate targeting NANOG with different techniques, which is a promising treatment strategy for cancer treatment.