New emerging targets in osteosarcoma therapy: PTEN and PI3K/Akt crosstalk in carcinogenesis.

Osteosarcoma (OS) is a malignant bone carcinoma that affects people in childhood and adulthood. The heterogeneous nature and chromosomal instability represent certain characteristics of OS cells. These cancer cells grow and migrate abnormally, making the prognosis undesirable for patients. Conventional and current treatments fail to completely eradicate tumor cells, so new therapeutics targeting genes may be considered. PI3K/Akt is a regulator of events such as growth, cell death, migration, and differentiation, and its expression changes during cancer progression. PTEN reduces PI3K/Akt expression, and its mutations and depletions have been reported in various tumors. Experimental evidence shows that there is upregulation of PI3K/Akt and downregulation of PTEN in OS. Increasing PTEN expression may suppress PI3K/Akt to minimize tumorigenesis. In addition, PI3K/Akt shows a positive association with growth, metastasis, EMT and metabolism of OS cells and inhibits apoptosis. Importantly, overexpression of PI3K/Akt causes drug resistance and radio-resistance and its level can be modulated by miRNAs, lncRNAs and circRNAs. Silencing PI3K/Akt by compounds and drugs can suppress OS. Here, we review in detail the function of the PTEN/PI3K/Akt in OS, revealing its biological function, function in tumor progression, resistance to therapy, and pharmacological significance.

STAT3 signaling in prostate cancer progression and therapy resistance: An oncogenic pathway with diverse functions.

The categorization of cancers demonstrates that prostate cancer is the most common malignancy in men and it causes high death annually. Prostate cancer patients are diagnosed mainly via biomarkers such as PSA test and patients show poor prognosis. Prostate cancer cells rapidly diffuse into different parts of body and their metastasis is also a reason for death. Current therapies for prostate cancer patients include chemotherapy, surgery and radiotherapy as well as targeted therapy. The progression of prostate cancer cells is regulated by different factors that STAT3 signaling is among them. Growth factors and cytokines such as IL-6 can induce STAT3 signaling and it shows carcinogenic impact. Activation of STAT3 signaling occurs in prostate cancer and it promotes malignant behavior of tumor cells. Induction of STAT3 signaling increases glycolysis and proliferation of prostate cancer cells and prevents apoptosis. Furthermore, STAT3 signaling induces EMT mechanism in increasing cancer metastasis. Activation of STAT3 signaling stimulates drug resistance and the limitation of current works is lack of experiment related to role of STAT3 signaling in radio-resistance in prostate tumor. Calcitriol, capsazepine and ß-elemonic are among the compounds capable of targeting STAT3 signaling and its inhibition in prostate cancer therapy. In addition to natural products, small molecules targeting STAT3 signaling have been developed in prostate cancer therapy.

Low-dose sumatriptan improves the outcome of acute mesenteric ischemia in rats via downregulating kynurenine.

BACKGROUND: Mesenteric ischemia has remained without effective pharmacological management for many years. Sumatriptan, an abortive medication for migraine and cluster headaches, has potent anti-inflammatory properties and ameliorated organ ischemia in previous animal studies. Similarly, inhibition of the kynurenine pathway ameliorated renal and myocardial ischemia/reperfusion (I/R) in many preclinical studies. Herein, we assessed the effect of sumatriptan on experimental mesenteric I/R and investigated whether kynurenine pathway inhibition is a mechanism underlying its action. METHODS: Ischemia was induced by ligating the origin of the superior mesenteric artery (SMA) and its anastomosis with the inferior mesenteric artery (IMA) with bulldog clamps for 30 min. Ischemia was followed by 1 h of reperfusion. Sumatriptan (0.1, 0.3, and 1 mg/kg ip) was injected 5 min before the reperfusion phase, 1-methyltryptophan (1-MT) (100 mg/kg iv) was used to inhibit kynurenine production. At the end of the reperfusion phase, samples were collected from the jejunum of rats for H&E staining and molecular assessments. RESULTS: Sumatriptan improved the integrity of intestinal mucosa after I/R, and 0.1 mg/kg was the most effective dose of sumatriptan in this study. Sumatriptan decreased the increased levels of TNF-α, kynurenine, and p-ERK but did not change the decreased levels of NO. Furthermore, sumatriptan significantly increased the decreased ratio of Bcl2/Bax. Similarly, 1-MT significantly decreased TNF-α and kynurenine and protected against mucosal damage. CONCLUSIONS: This study demonstrated that sumatriptan has protective effects against mesenteric ischemia and the kynurenine inhibition is potentially involved in this process. Therefore, it can be assumed that sumatriptan has the potential to be repurposed as a treatment for acute mesenteric ischemia.

Non-coding RNAs in EMT regulation: Association with tumor progression and therapy response.

RNA molecules lacking capacity in protein translation, are known as non-coding RNAs (ncRNAs). Growth, differentiation and migration are influenced by ncRNAs in cells. The abnormal expression of ncRNAs contributes to development of diseases, especially cancer. On the other hand, EMT is a vital mechanism for cancer invasion and diffusion in body. In this manuscript, role of ncRNAs in EMT regulation and subsequent effect on cancer progression is investigated. The miRNAs regulate EMT by affecting signaling pathways including PI3K/Akt and PTEN to modulate cancer metastasis. Furthermore, miRNA and EMT interaction has close association with drug sensitivity of tumor cells. LncRNAs can affect EMT via targeting ZEB1/2, Twist and Snail among others and similarly, based on the impact on EMT, sensitivity of cancer cells to therapy increases or decreases. CircRNAs regulate both drug sensitivity and metastasis of cancers by affecting EMT mechanism. Noteworthy, circRNAs and lncRNAs are capable of sponging miRNAs in modulating EMT mechanism. Exosomes belong to extracellular vesicles with low size that can be secreted by cells in transferring genetic materials. The transfer of ncRNAs by exosomes is performed and they can also regulate EMT in cancer progression. Finally, ncRNAs regulating EMT mechanism are used for cancer diagnosis and prognosis.

STAT3-EMT axis in tumors: Modulation of cancer metastasis, stemness and therapy response.

Epithelial-to-mesenchymal transition (EMT) mechanism is responsible for metastasis of tumor cells and their spread to various organs and tissues of body, providing undesirable prognosis. In addition to migration, EMT increases stemness and mediates therapy resistance. Hence, pathways involved in EMT regulation should be highlighted. STAT3 is an oncogenic pathway that can elevate growth rate and migratory ability of cancer cells and induce drug resistance. The inhibition of STAT3 signaling impairs cancer progression and promotes chemotherapy-mediated cell death. Present review focuses on STAT3 and EMT interaction in modulating cancer migration. First of all, STAT3 is an upstream mediator of EMT and is able to induce EMT-mediated metastasis in brain tumors, thoracic cancers and gastrointestinal cancers. Therefore, STAT3 inhibition significantly suppresses cancer metastasis and improves prognosis of patients. EMT regulators such as ZEB1/2 proteins, TGF-ß, Twist, Snail and Slug are affected by STAT3 signaling to stimulate cancer migration and invasion. Different molecular pathways such as miRNAs, lncRNAs and circRNAs modulate STAT3/EMT axis. Furthermore, we discuss how STAT3 and EMT interaction affects therapy response of cancer cells. Finally, we demonstrate targeting STAT3/EMT axis by anti-tumor agents and clinical application of this axis for improving patient prognosis.

Long non-coding RNAs and exosomal lncRNAs: Potential functions in lung cancer progression, drug resistance and tumor microenvironment remodeling.

Among the different kinds of tumors threatening human life, lung cancer is one that is commonly observed in both males and females. The aggressive behavior of lung cancer and interactions occurring in tumor microenvironment enhances the malignancy of this tumor. The lung tumor cells have demonstrated capacity in developing chemo- and radio-resistance. LncRNAs are a category of non-coding RNAs that do not encode proteins, but their aberrant expression is responsible for tumor development, especially lung cancer. In the present review, we focus on both lncRNAs and exosomal lncRNAs in lung cancer, and their ability in regulating proliferation and metastasis. Cell cycle progression and molecular mechanisms related to lung cancer metastasis such as EMT and MMPs are regulated by lncRNAs. LncRNAs interact with miRNAs, STAT, Wnt, EZH2, PTEN and PI3K/Akt signaling pathways to affect progression of lung cancer cells. LncRNAs demonstrate both tumor-suppressor and tumor-promoting functions in lung cancer. They can be considered as biomarkers in lung cancer and especially exosomal lncRNAs present in body fluids are potential tools for minimally invasive diagnosis. Furthermore, we discuss regulation of lncRNAs by anti-cancer drugs and genetic tools as well as the role of these factors in therapy response of lung cancer cells.

Targeting Nrf2 in ischemia-reperfusion alleviation: From signaling networks to therapeutic targeting.

The nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of redox balance and it responds to various cell stresses that oxidative stress is the most well-known one. The Nrf2 should undergo nuclear translocation to exert its protective impacts and decrease ROS production. On the other hand, ischemic/reperfusion (I/R) injury is a pathological event resulting from low blood flow to an organ and followed by reperfusion. The I/R induces cell injury and organ dysfunction. The present review focuses on Nrf2 function in alleviation of I/R injury. Stimulating of Nrf2 signaling ameliorates I/R injury in various organs including lung, liver, brain, testis and heart. The Nrf2 enhances activity of antioxidant enzymes to reduce ROS production and prevent oxidative stress-mediated cell death. Besides, Nrf2 reduces inflammation via decreasing levels of pro-inflammatory factors including IL-6, IL-1ß and TNF-α. Nrf2 signaling is beneficial in preventing apoptosis and increasing cell viability. Nrf2 induces autophagy to prevent apoptosis during I/R injury. Furthermore, it can interact with other molecular pathways including PI3K/Akt, NF-κB, miRNAs, lncRNAs and GSK-3ß among others, to ameliorate I/R injury. The therapeutic agents, most of them are phytochemicals such as resveratrol, berberine and curcumin, induce Nrf2 signaling in I/R injury alleviation.

Non-coding RNAs and macrophage interaction in tumor progression.

The macrophages are abundantly found in TME and their M2 polarization is in favor of tumor malignancy. On the other hand, non-coding RNAs (ncRNAs) can modulate macrophage polarization in TME to affect cancer progression. The miRNAs can dually induce/suppress M2 polarization of macrophages and by affecting various molecular pathways, they modulate tumor progression and therapy response. The lncRNAs can affect miRNAs via sponging and other molecular pathways to modulate macrophage polarization. A few experiments have also examined role of circRNAs in targeting signaling networks and affecting macrophages. The therapeutic targeting of these ncRNAs can mediate TME remodeling and affect macrophage polarization. Furthermore, exosomal ncRNAs derived from tumor cells or macrophages can modulate polarization and TME remodeling. Suppressing biogenesis and secretion of exosomes can inhibit ncRNA-mediated M2 polarization of macrophages and prevent tumor progression. The ncRNAs, especially exosomal ncRNAs can be considered as non-invasive biomarkers for tumor diagnosis.

Molecular landscape of c-Myc signaling in prostate cancer: A roadmap to clinical translation.

The c-Myc signaling is a new emerging target in cancer therapy. Activation of c-Myc signaling leads to cancer growth and invasion in vitro and in vivo. The stability of c-Myc can also mediate drug resistance and radioresistance in cancers. The apoptosis inhibition and enhancing cell cycle progression are mediated by c-Myc overexpression. On the other hand, prostate cancer (PC) is the most common cancer in men and causes high death. The present review focuses on c-Myc signaling in PC. The c-Myc overexpression is in favor of PC growth and migration. Upon c-Myc inhibition, apoptosis and cell cycle arrest (G0/G1 phase) occur in PC cells. The c-Myc induces glycolysis in enhancing PC growth. Besides, stability and overexpression of c-Myc can mediate resistance of PC cells to chemotherapy and radiotherapy. The inhibition of c-Myc by both anti-tumor agents and genetic tools suppress PC progression. The miRNAs, lncRNAs, circRNAs and other factors such as PI3K/Akt can act as upstream regulator of c-Myc signaling. The c-Myc can function as independent prognostic and diagnostic factor in PC patients. The c-Myc upregulation is associated with reduced overall survival, clinical stage, lymph node metastasis and undesirable prognosis of PC patients.

Key plasma microRNAs variations in patients with Plasmodium vivax malaria in Iran.

Introduction: As the cause of RBC infection and splenomegaly, malaria remains a major parasitic disease in the world. New specific biomarkers such as MicroRNAs (miRNAs) are developed to accurately diagnose malaria and clarify its pathologic changes. This study aimed at evaluating changes in the plasma miRNAs markers of Plasmodium vivax in patients with malaria in Chabahar, Iran. Materials and methods: For the present descriptive-analytical study conducted in 2018, we collected blood samples from 20 individuals. Real-time quantitative Polymerase Chain Reaction (RT-qPCR) was used to measure the plasma levels of miR-145, miR-155, miR-191 and miR-223-3p. Results: The 2-ΔΔCT method of Real-time PCR showed the plasma levels of miR-223, miR-145 and miR-155 to respectively be 5.6, 16.9 and 1.7 times higher in patients with P. vivax compared to those in healthy individuals. The expressions of all the three miRNAs significantly increased in patients with malaria compared to in the controls (P < 0.05). The expression of miR-191 was 1.405 times higher in patients with malaria compared to that in the controls, although the difference was statistically insignificant. Conclusion: The present study found P. vivax to change host miRNAs such as miR-223, miR-145 and miR-155. These small molecules thus appeared to constitute biomarkers for P. vivax malaria assessment.