Search

Background: One of the cancers that occur most frequently around the world is colorectal cancer (CRC). STAT6 transcription factor is involved in cellular multipotency, tumor cell growth, drug resistance, stemness, and migration, showing potential as a cancer therapy target for a variety of cancers, including CRC. In this regard, the current study aimed to investigate the effect of STAT6 silencing via small interference RNA (siRNA) in combination with 5-FU on CRC development. Methods: The MTT assay and the Annexin V/PI staining were used to examine cell proliferation and apoptosis induction, respectively. Flow cytometry was performed to investigate cell cycle progression. Wound healing assays were also used to examine HT-29 cell migration. A colony formation assay was used to examine cell stemness features of HT-29 cells. The qRT-PCR was used to measure the gene expression levels in the samples. Results: Apoptosis induction by STAT6 inhibition significantly improved the HT-29 cell chemosensitivity to 5-FU. Both caspase-9 apoptotic gene and Bax/Bcl-2 ratio were upregulated when STAT6 suppression and 5-FU were combined. Additionally, combination therapy led to cell cycle arrest at the sub-G1 phase in CRC cells. The combined therapy also significantly reduced MMP9 expression, which in turn reduced the migration of HT-29 cells. Furthermore, STAT6 knockdown inhibited HT-29 cell colony formation by reducing the expression of the Sox2 and CD44 genes, either alone or in combination with 5-FU. Conclusions: The findings show that combination therapy of 5-FU and STAT6 silencing may be an effective treatment for patients with CRC.

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.

Immune checkpoints are vital molecules that regulate T-cell function by activation or inhibition. Among the immune checkpoint molecules, the B7-family proteins are significantly involved in the immune escape of tumor cells. By binding to inhibitory receptors, they can suppress T-cell-mediated immunity. B7-family proteins are found at various stages of tumor microenvironment formation and promote tumorigenesis and tumor progression. B7-H6 (encoded by gene NCR3LG1) is a prominent member of the family. It has unique immunogenic properties and is involved in natural killer (NK) cell immunosurveillance by binding to the NKp30 receptor. High B7-H6 expression in certain tumor types and shortage of or low expression in healthy cells - except in cases of inflammatory or microbial stimulation - have made the protein an attractive target of research activities in recent years. The avoidance of NK-mediated B7-H6 detection is a mechanism through which tumor cells escape immune surveillance. The stimulation of tumorigenesis occurs by suppressing caspase cascade initiation and anti-apoptosis activity stimulation via the STAT3 pathway. The B7-H6-NKp30 complex on the tumor membrane activates the NK cells and releases both tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). B7-H6 is highly expressed in a wide range of tumor cells, including glioma, hematologic malignant tumors, and breast cancer cells. Clinical examination of cancer patients indicated that the expression of B7-H6 is related to distant metastasis status and permits postoperative prognosis. Because of its unique properties, B7-H6 has a high potential be utilized as a biological marker for cancer diagnosis and prognosis, as well as a target for novel treatment options.

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.

Simple Summary Colorectal cancer (CRC) begins when normal cells turn out of balance, and a tumor is formed in the lining of the colon or rectum. Cytotoxic T-lymphocyte protein 4 (CTLA-4) is a potent molecule that could inhibit T cell activation. Here, we analyzed this molecule in the tissue samples and cell lines of colorectal cancer to reveal the mechanism of this inhibitory molecule in CRC. Our result showed an increasing trend of CTLA-4 in tissues and cell lines. Finally, capecitabine as an approved drug in CRC could suppress this inhibitory molecule. It can be concluded that the inhibition of this inhibitory molecule can re-active the immune cells, especially T cells, in CRC patients, which boosts the immune cells against the tumor. Abstract Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory immune checkpoint that can be expressed in tumor-infiltrating lymphocytes and colorectal cancer (CRC) cells. This immune checkpoint can attenuate anti-tumoral immune responses and facilitate tumor growth and metastasis. Although capecitabine is an effective chemotherapeutic agent for treating CRC, its effect on the tumoral CTLA-4 expression remains unclear. In the current research, we applied the GSE110224 and GSE25070 datasets to characterize CTLA-4 expression in CRC patients. Then, we analyzed CTLA-4 expression in CRC samples, HT-29, HCT-166, and SW480 cell lines using real-time PCR. Our bioinformatic results have highlighted the overexpression of CTLA-4 in the CRC tissues compared to the adjacent non-tumoral tissues. Our in vitro studies have indicated that SW480 cells can substantially overexpress CTLA-4 compared to HT-29 and HCT 116 cells. In addition, capecitabine can remarkably downregulate the expression of CTLA-4 in SW480 cells. Collectively, capecitabine can inhibit the expression of CTLA-4 in CRC cells and might bridge the immunotherapy approaches with chemotherapy.

In the treatment of breast cancer (BC), as an important type of cancer in women, the specific cells, called cancer stem cells (CSCs), are the reason of failure and metastasis. So, targeting CSCs can be used as a novel strategy in cancer therapy in addition to common therapeutic strategies. According to the importance of CSCs, we tried to find a correlation between stemness and metastatic characteristics of BC cells, to address whether CSCs are a potential target for cancer therapy. Here, we evaluated the NANOG inhibition by siRNA and the increase of Let-7a levels by miRNA mimic in breast cancer cells and the effects of these changes on biologic aspects like cell apoptosis, stemness and invasion. Our results showed that the inhibition of NANOG combined with Let-7a restoration contributed to significant decrease in malignant phenotypes and stemness feature of BC cells. In conclusion, these findings showed that the combination of Let-7a miRNA mimic and Nanog siRNA could be exploited as a new treatment strategy to improve the cancer therapy outcome.

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/β-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.

Lung cancer is one of the most common cancers and its incidence is rising around the world. Various studies suggest that miR-330 acts as a tumor-suppressor microRNA (miRNA) in different types of cancers, but precisely how has remained unclear. In this study, we investigate miR-330 expression in lung cancer patient samples, as well as in vitro, by studying how normalization of miR-330 expression affects lung cancer cellular phenotypes such as viability, apoptosis, proliferation, and migration. We establish that low miR-330 expression predicts poor lung cancer prognosis. Stable restoration of reduced miR-330 expression in lung cancer cells reduces cell viability, increases the fraction of apoptotic cells, causes G2/M cell cycle arrest, and inhibits cell migration. These findings are substantiated by increased mRNA and protein expression of markers for apoptosis via the intrinsic pathway, such as caspase 9, and decreased mRNA and protein expression of markers for cell migration, such as vimentin, C-X-C chemokine receptor type 4, and matrix metalloproteinase 9. We showed that reduced miR-330 expression predicts poor lung cancer survival and that stable restoration of miR-330 expression in lung cancer cells has a broad range of tumor-suppressive effects. This indicates that miR-330 is a promising candidate for miRNA replacement therapy for lung cancer patients. Refereed/Peer-reviewed

Colorectal cancer (CRC) is considered one of the leading types of cancer in the world. CD133, as a cancer stem cell marker, has a pivotal role in the development of drug resistance, migration, and stemness properties of CRC cells. This study was designed to check the combined effect of CD133 siRNA and Oxaliplatin on proliferation, migration, apoptosis, and stemness properties of CRC cells in the HT-29 cell line. MTT assay was performed to define the combined effect of CD133 siRNA and Oxaliplatin on the viability of HT-29 cells, and it showed that the combination of CD133 siRNA and Oxaliplatin could reduce the IC50 of this drug from 32.85 to 19.75 nmol. In order to figure out the effect of this combination therapy on CD133 expression at the gene and protein level, qRT-PCR and western blot were exploited, respectively. The results demonstrated that the silencing of CD133 could reduce the relative expression of this marker to about 0.00001 compared to the control group and reduce the protein level to 0.01. The ability of cell migration was tested by wound healing assay as well. Also, colony formation and sphere formation were conducted to assess the stemness properties in the combination group. Flow cytometry was conducted to investigate the apoptosis (15%), cell cycle (about 10% arresting in G0-G1 phase), and surface expression of CD133 in different groups (from 39.3% in the control group to 2.41 in the combination group). Finally, the expression of migration-, and stemness-associated genes were measured by qRT-PCR. We indicated that silencing of CD133 reduces the migration and stemness properties of colorectal cancerous cells. This suppression makes HT-29 cells more sensitive to Oxaliplatin and reduces the effective dose of this chemical drug. Therefore, the suppression of CD133 in combination with Oxaliplatin treatment might be a promising therapeutic approach in the treatment of colorectal cancer.

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.

Gynecologic cancers account for approximately 11% of the newly diagnosed cancers in women in the United States and for 18% globally. The presence of tumor-infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICIs), including anti programmed cell death protein-1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), and anticytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), which have been approved for treating different types of malignancies. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host–tumor interaction. There are several the US food and drug administration (FDA)-approved ICIs targeting PD-1, including pembrolizumab and nivolumab, as well as those targeting PD-L1, including avelumab, atezolizumab, and durvalumab for melanoma, renal cell cancer, colorectal cancer, head and neck cancer, cervix cancer, urothelial cancer, and lung cancer. Current pre-clinical and clinical studies assessing PD-1/PD-L1 inhibitors in several gynecologic cancers have reported significant antitumor activity. In this review, we investigate pre-clinical and clinical studies that describe the safety and efficacy of anti-PD-1/PD-L1 antibodies, with a particular focus on ongoing clinical trials, analyzing the oncological outcome and adverse effects of ICIs in gynecologic cancers.

Despite improved therapeutic strategies for early-stage breast cancer, the most common cancer type in women, relapse remains common and the underlying mechanisms for this progression remain poorly understood. To gain more insight, we studied the DNA-binding protein HMGA2 in breast cancer development and stemness. We demonstrated that HMGA2 is overexpressed in breast cancer tissues at the mRNA and protein levels (P value

Breast cancer (BC) is the most common type of malignancy in women. A subset of breast cancers show resistance to endocrine-based therapies. The estrogen receptor (ER) plays a critical role in developing hormone-dependent BC. Loss of ER contributes to resistance to tamoxifen therapy and may contribute to mortality. Thus, it is crucial to overcome this problem. Here, using luciferase reporter assays, qRT-PCR, and Western blot analyses, we demonstrate that the microRNA miR-486–5p targets HMGA1 mRNA, decreasing its mRNA and protein levels in ER-positive (ER+) BC cells. Consistently, miR-486–5p is significantly downregulated, whereas HMGA1 is considerably upregulated in ER+ BC samples. Remarkably, while both miR-486–5p and tamoxifen individually cause G2/M cell cycle arrest, combination treatment synergistically causes profound cell death, specifically in tamoxifen-resistant ER+ cells but not in tamoxifen-sensitive ER+ cells. Combined treatment with miR-486–5p and tamoxifen also additively reduces cell migration, invasion, colony formation, mammary spheroid formation and a CD24-CD44+ cell population, representing decreased cancer stemness. However, these phenomena are independent of the tamoxifen responsiveness of the ER+ BC cells. Thus, miR-486–5p and tamoxifen exhibit additive and synergistic tumor-suppressive effects, most importantly causing profound cell death specifically in tamoxifen-resistant BC cells. Therefore, our work suggests that combining miR-486–5p replacement therapy with tamoxifen treatment is a promising strategy to treat endocrine therapy-resistant BC. Breast cancer (BC) is the most common type of malignancy in women. A subset of breast cancers show resistance to endocrine-based therapies. The estrogen receptor (ER) plays a critical role in developing hormone-dependent BC. Loss of ER contributes to resistance to tamoxifen therapy and may contribute to mortality. Thus, it is crucial to overcome this problem. Here, using luciferase reporter assays, qRT-PCR, and Western blot analyses, we demonstrate that the microRNA miR-486–5p targets HMGA1 mRNA, decreasing its mRNA and protein levels in ER-positive (ER+) BC cells. Consistently, miR-486–5p is significantly downregulated, whereas HMGA1 is considerably upregulated in ER+ BC samples. Remarkably, while both miR-486–5p and tamoxifen individually cause G2/M cell cycle arrest, combination treatment synergistically causes profound cell death, specifically in tamoxifen-resistant ER+ cells but not in tamoxifen-sensitive ER+ cells. Combined treatment with miR-486–5p and tamoxifen also additively reduces cell migration, invasion, colony formation, mammary spheroid formation and a CD24-CD44+ cell population, representing decreased cancer stemness. However, these phenomena are independent of the tamoxifen responsiveness of the ER+ BC cells. Thus, miR-486–5p and tamoxifen exhibit additive and synergistic tumor-suppressive effects, most importantly causing profound cell death specifically in tamoxifen-resistant BC cells. Therefore, our work suggests that combining miR-486–5p replacement therapy with tamoxifen treatment is a promising strategy to treat endocrine therapy-resistant BC.

MicroRNAs (miRNAs) are important molecular regulatorsof cellular signaling and behavior. They alter gene expression by targeting messenger RNAs, including those encoding transcriptional regulators, such as HMGA2. While HMGA2 is oncogenic in various tumors, miRNAs may be oncogenic or tumor suppressive. Here, we investigate the expression of HMGA2 and the miRNA miR-330 in a patient with colorectal cancer (CRC) samples and their effects on oncogenic cellular phenotypes. We found that HMGA2 expression is increased and miR-330 expression is decreased in CRCs and each predicts poor long-term patient survival. Stably increased miR-330 expression in human colorectal cancer cells (HCT116) and SW480 CRC cell lines downregulate the oncogenic expression of HMGA2, a predicted miR-330 target. Additionally, this promotes apoptosis and decreases cell migration and viability. Consistently, it also decreases protein-level expression of markers for epithelial-to-mesenchymal-transition (Snail-1, E-cadherin, and Vascular endothelial growth factor receptors) and transforming growth factor β signaling (SMAD3), as well as phospho- Protein kinase B (AKT) and phospho-STAT3 levels. We conclude that miR-330 acts as a tumor suppressor miRNA in CRC by suppressing HMGA2 expression and reducing cell survival, proliferation, and migration. Thus, we identify miR-330 as a promising candidate for miRNA replacement therapy for patients with CRC. Refereed/Peer-reviewed

The subjection of DNA to numerous lethal damages is threatening for the stability and integrity of the whole body genome. DNA damage response (DDR) is a critical phosphorylation-based signaling pathway developed for the maintaining of the genome against these threatens. Recent studies showed that various targets of DDR are involved in the activation of autophagy, as one of the important effectors of this signaling. The interplay between DDR and autophagy may have a critical role in the pathogenesis of various malignancies such as colorectal cancer, which can be a basement for the designing novel therapeutic strategies for combating this cancer type. On the other hand, autophagy is also demonstrated to be contributed to the regulation of DDR components. Therefore, in this review article, we will discuss the crosstalk between DDR and autophagy and their exact function in the pathogenesis of various human cancer types, with special attention on colorectal cancer.

The coronavirus disease-2019 (COVID-19) pandemic has caused an enormous loss of lives. Various clinical trials of vaccines and drugs are being conducted worldwide; nevertheless, as of today, no effective drug exists for COVID-19. The identification of key genes and pathways in this disease may lead to finding potential drug targets and biomarkers. Here, we applied weighted gene co-expression network analysis and LIME as an explainable artificial intelligence algorithm to comprehensively characterize transcriptional changes in bronchial epithelium cells (primary human lung epithelium (NHBE) and transformed lung alveolar (A549) cells) during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our study detected a network that significantly correlated to the pathogenicity of COVID-19 infection based on identified hub genes in each cell line separately. The novel hub gene signature that was detected in our study, including PGLYRP4 and HEPHL1, may shed light on the pathogenesis of COVID-19, holding promise for future prognostic and therapeutic approaches. The enrichment analysis of hub genes showed that the most relevant biological process and KEGG pathways were the type I interferon signaling pathway, IL-17 signaling pathway, cytokine-mediated signaling pathway, and defense response to virus categories, all of which play significant roles in restricting viral infection. Moreover, according to the drug–target network, we identified 17 novel FDA-approved candidate drugs, which could potentially be used to treat COVID-19 patients through the regulation of four hub genes of the co-expression network. In conclusion, the aforementioned hub genes might play potential roles in translational medicine and might become promising therapeutic targets. Further in vitro and in vivo experimental studies are needed to evaluate the role of these hub genes in COVID-19.

Mitogen-activated protein kinase (MAPK) signal transduction, as a highly conserved signaling pathway, is reported to be involved in various biological events, including metabolic reprogramming, cell proliferation, survival, and differentiation. Mutations in key molecules involved in MAPK/ERK signaling and dysregulation of this pathway are very common events in various human malignancies, which make the MAPK signaling a crucial signaling pathway participating in the regulation of glucose uptake by malignant cells and tumorigenesis. MicroRNAs (miRNAs), as small non-coding RNAs, are critical regulators of gene expression that play key roles in cancer initiation and progression. On the other hand, these small RNAs mutually regulate the MAPK signaling which is often overexpressed in the case of cancer progression; suggesting that crosstalk between miRNAs and this signaling pathway plays a pivotal role in the development of human cancers. Some miRNAs such as miR-20b, miR-34c-3p, miR-152, miR-181a, and miR-302b through inhibiting MAPK signaling, and miR-193a-3p, miR-330-3p, and miR-592 by activating this signaling pathway, play imperative roles in tumorigenesis. Therefore, in this review, we aimed to focus on the interplay between miRNAs and MAPK signaling in the various steps of tumorigenesis, including metabolic regulation, cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. Mitogen-activated protein kinase (MAPK) signal transduction, as a highly conserved signaling pathway, is reported to be involved in various biological events, including metabolic reprogramming, cell proliferation, survival, and differentiation. Mutations in key molecules involved in MAPK/ERK signaling and dysregulation of this pathway are very common events in various human malignancies, which make the MAPK signaling a crucial signaling pathway participating in the regulation of glucose uptake by malignant cells and tumorigenesis. MicroRNAs (miRNAs), as small non-coding RNAs, are critical regulators of gene expression that play key roles in cancer initiation and progression. On the other hand, these small RNAs mutually regulate the MAPK signaling which is often overexpressed in the case of cancer progression; suggesting that crosstalk between miRNAs and this signaling pathway plays a pivotal role in the development of human cancers. Some miRNAs such as miR-20b, miR-34c-3p, miR-152, miR-181a, and miR-302b through inhibiting MAPK signaling, and miR-193a-3p, miR-330-3p, and miR-592 by activating this signaling pathway, play imperative roles in tumorigenesis. Therefore, in this review, we aimed to focus on the interplay between miRNAs and MAPK signaling in the various steps of tumorigenesis, including metabolic regulation, cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance.

Introduction: Coronavirus disease 2019 (COVID-19) is responsible for severe acute respiratory syndrome. The present study planned to evaluate the accuracy of laboratory parameters and clinical findings in predication of the infected cases through RT-PCR. Methods: All related laboratory tests of 180 cases (62.8% male and 37.2% female) with an average of 62 years old (45.3-69) were performed by several laboratory techniques. The obtained results as well as other clinical and biography findings of the patients during the treatment and recovery were compared and analyzed to find out the possible relationship among the considered parameters. Results: The considered hematological and biochemistry factors were completely different in all cases regardless to their health and lifestyle condition, including being at ICU, being addict or not, whether having previous diseases or not and others. Conclusion: COVID-19 has brought a huge burden to the health system and infected patients, especially those who have a background of chronic diseases or addicted to some drugs.

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/β-catenin, Notch, TGF-β, 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.

Introduction: Failure and recurrence in breast cancer treatment cause a great obstacle in cancer therapy and identification of cell population named cancer stem cells (CSCs) in the tumor can be led us to define it as target in novel therapeutic strategy. Objectives: The aim of this study is the finding of correlation between stemness and metastatic characteristic, also knowing CSCs as a potential target of therapy because of its developmental behavior and similarities with normal stem cells. Materials and Methods: Here, we focus on the expression of NANOG in breast CSCs, a key molecule in the physiological process of stem cells and the Let-7a that is involved in the differentiation of the cells. Results: In this work, we found that NANOG was highly expressed in SKBR3 and down-regulation of let-7a, as a differentiation miRNA, was found in MDA-MB-468 cells. Conclusion: It will be critical for the developing of effective anti-tumor drugs, utilizing mentioned concepts. Inhibition of NANOG in combination with Let-7a up-regulation can help to decrease the stemness and increase the differentiation of CSCs. The decrease of stemness and increase of differentiation initiate the apoptotic process. So, modification in the mechanism of apoptosis beside anti-cancer drugs provide a good preclinical study goal. However, in order to these drugs become clinical, the problems of their side effects and toxicity must be solved. Differentiation of CSCs provides an optimal condition to activity of immune cells which never let them escape from immune cells by alteration of immunogenicity.