Plasma microRNA-195, -34c, and - 1246 as novel biomarkers for the diagnosis of trastuzumab-resistant HER2-positive breast cancer patients.

Recently, miRNAs have been regarded as potential candidates for mediating therapeutic functions by targeting genes related to drug response. In this study, we suggested that plasma miRNAs may be correlated with response to trastuzumab in HER2-positive breast cancer patients. To determine whether miR-195, miR-23b-3p, miR-1246, and miR-34c-3p are involved in trastuzumab resistance, we screened their expressions in the BT-474 cell line, which was followed by plasma analysis from 20 trastuzumab-resistant HER2-positive breast cancer patients and 20 nonresistance subjects. Then, TargetScan, Pictar, and miRDB were applied to find the possible targets of the selected miRNAs. In addition, the expression status of admitted targets was evaluated. Our results showed that in resistant BT-474 cells, miR-1246, and miR-23b-3p were significantly upregulated, and miR-195-5p and miR-34c-3p were downregulated. In plasma analysis, we found miR-195-5p, miR-34c-3p, and miR-1246 meaningfully diminished in the resistant group, while the expression of miR-23b-3p was not statistically different. The expression levels of confirmed targets by qRT-PCR showed that the expression of RAF1, AKT3, c-MET, CCND1, PHLPP2, MYB, MAP2K1, and PTEN was significantly upregulated, while the expression of CCNG2 was significantly downregulated. The networks of miRNAs with their confirmed targets improved comprehension of miRNA-mediated therapeutic responses to trastuzumab and might be proposed for more characterization of miRNA functions. Moreover, these data indicated that miR-195-5p, miR-34c-3p, and miR-1246 could be possible biomarkers for prognosis and early detection of the trastuzumab-resistant group from the sensitive group of HER2-positive breast cancer patients.

MicroRNAs as the pivotal regulators of cisplatin resistance in head and neck cancers.

Although, there is a high rate of good prognosis in early stage head and neck tumors, about half of these tumors are detected in advanced stages with poor prognosis. A combination of chemotherapy, radiotherapy, and surgery is the treatment option in head and neck cancer (HNC) patients. Although, cisplatin (CDDP) as the first-line drug has a significant role in the treatment of HNC patients, CDDP resistance can be observed in a large number of these patients. Therefore, identification of the molecular mechanisms involved in CDDP resistance can help to reduce the side effects and also provides a better therapeutic management. MicroRNAs (miRNAs) as the post-transcriptional regulators play an important role in drug resistance. Therefore, in the present review we investigated the role of miRNAs in CDDP response of head and neck tumors. It has been reported that the miRNAs exerted their roles in CDDP response by regulation of signaling pathways such as WNT, NOTCH, PI3K/AKT, TGF-ß, and NF-kB as well as apoptosis, autophagy, and EMT process. The present review paves the way to suggest a non-invasive miRNA based panel marker for the prediction of CDDP response among HNC patients. Therefore, such diagnostic miRNA based panel marker reduces the CDDP side effects and improves the clinical outcomes of these patients following an efficient therapeutic management.

PRC2 mediated KLF2 down regulation: a therapeutic and diagnostic axis during tumor progression.

Surgery and chemo-radiotherapy are used as the common first-line treatment options in many cancers. However, tumor relapse is observed in many cancer patients following such first-line treatments. Therefore, targeted therapy according to the molecular cancer biology can be very important in reducing tumor recurrence. In this regard, a wide range of monoclonal antibodies against the growth factors and their receptors can offer more targeted treatment in cancer patients. However, due to the importance of growth factors in the normal biology of body cells, side effects can also be observed following the application of growth factor inhibitors. Therefore, more specific factors should be introduced as therapeutic targets with less side effects. Krüppel-like factors 2 (KLF2) belongs to the KLF family of transcription factors that are involved in the regulation of many cellular processes. KLF2 deregulations have been also reported during the progression of many tumors. In the present review we discussed the molecular mechanisms of KLF2 during tumor growth and invasion. It has been shown that the KLF2 as a tumor suppressor is mainly inhibited by the non-coding RNAs (ncRNAs) through the polycomb repressive complex 2 (PRC2) recruitment. This review is an effective step towards introducing the KLF2 as a suitable diagnostic and therapeutic target in cancer patients.

Molecular mechanisms of microRNA-216a during tumor progression.

MicroRNAs (miRNAs) as the members of non-coding RNAs family are involved in post-transcriptional regulation by translational inhibiting or mRNA degradation. They have a critical role in regulation of cell proliferation and migration. MiRNAs aberrations have been reported in various cancers. Considering the importance of these factors in regulation of cellular processes and their high stability in body fluids, these factors can be suggested as suitable non-invasive markers for the cancer diagnosis. MiR-216a deregulation has been frequently reported in different cancers. Therefore, in the present review we discussed the molecular mechanisms of the miR-216a during tumor progression. It has been reported that miR-216a mainly functioned as a tumor suppressor through the regulation of signaling pathways and transcription factors. This review paves the way to suggest the miR-216a as a probable therapeutic and diagnostic target in cancer patients.

Cell cycle related long non-coding RNAs as the critical regulators of breast cancer progression and metastasis.

Cell cycle is one of the main cellular mechanisms involved in tumor progression. Almost all of the active molecular pathways in tumor cells directly or indirectly target the cell cycle progression. Therefore, it is necessary to assess the molecular mechanisms involved in cell cycle regulation in tumor cells. Since, early diagnosis has pivotal role in better cancer management and treatment, it is required to introduce the non-invasive diagnostic markers. Long non-coding RNAs (LncRNAs) have higher stability in body fluids in comparison with mRNAs. Therefore, they can be used as efficient non-invasive markers for the early detection of breast cancer (BCa). In the present review we have summarized all of the reported lncRNAs involved in cell cycle regulation in BCa. It has been reported that lncRNAs mainly affect the cell cycle in G1/S transition through the CCND1/CDK4-6 complex. Present review paves the way of introducing the cell cycle related lncRNAs as efficient markers for the early detection of BCa.

MicroRNAs as the Critical Regulators of Forkhead Box Protein Family in Pancreatic, Thyroid, and Liver Cancers.

The metabolism of human body is mainly regulated by the pancreas, liver, and thyroid using the hormones or exocrine secretions that affect the metabolic processes from food digestion to intracellular metabolism. Therefore, metabolic organ disorders have wide clinical symptoms that severely affect the quality of patient's life. The pancreatic, liver, and thyroid cancers as the main malignancies of the metabolic system have always been considered as one of the serious health challenges worldwide. Despite the novel therapeutic modalities, there are still significant high mortality and recurrence rates, especially in liver and pancreatic cancer patients which are mainly related to the late diagnosis. Therefore, it is required to assess the molecular bases of tumor progressions to introduce novel early detection and therapeutic markers in these malignancies. Forkhead box (FOX) protein family is a group of transcription factors that have pivotal roles in regulation of cell proliferation, migration, and apoptosis. They function as oncogene or tumor suppressor during tumor progression. MicroRNAs (miRNAs) are also involved in regulation of cellular processes. Therefore, in the present review, we discussed the role of miRNAs during pancreatic, thyroid, and liver tumor progressions through FOX regulation. It has been shown that miRNAs were mainly involved in tumor progression via FOXM and FOXO targeting. This review paves the way for the introduction of miR/FOX axis as an efficient early detection marker and therapeutic target in pancreatic, thyroid, and liver tumors.

MicroRNAs as the critical regulators of Doxorubicin resistance in breast tumor cells.

BACKGROUND: Chemotherapy is one of the most common treatment options for breast cancer (BC) patients. However, about half of the BC patients are chemotherapeutic resistant. Doxorubicin (DOX) is considered as one of the first line drugs in the treatment of BC patients whose function is negatively affected by multi drug resistance. Due to the severe side effects of DOX, it is very important to diagnose the DOX resistant BC patients. Therefore, assessment of molecular mechanisms involved in DOX resistance can improve the clinical outcomes in BC patients by introducing the novel therapeutic and diagnostic molecular markers. MicroRNAs (miRNAs) as members of the non-coding RNAs family have pivotal roles in various cellular processes including cell proliferation and apoptosis. Therefore, aberrant miRNAs functions and expressions can be associated with tumor progression, metastasis, and drug resistance. Moreover, due to miRNAs stability in body fluids, they can be considered as non-invasive diagnostic markers for the DOX response in BC patients. MAIN BODY: In the present review, we have summarized all of the miRNAs that have been reported to be associated with DOX resistance in BC for the first time in the world. CONCLUSIONS: Since, DOX has severe side effects; it is required to distinguish the non DOX-responders from responders to improve the clinical outcomes of BC patients. This review highlights the miRNAs as pivotal regulators of DOX resistance in breast tumor cells. Moreover, the present review paves the way of introducing a non-invasive panel of prediction markers for DOX response among BC patients.

Molecular mechanisms of the microRNA-132 during tumor progressions.

Cancer as one of the leading causes of human deaths has always been one of the main health challenges in the world. Despite recent advances in therapeutic and diagnostic methods, there is still a high mortality rate among cancer patients. Late diagnosis is one of the main reasons for the high ratio of cancer related deaths. Therefore, it is required to introduce novel early detection methods. Various molecular mechanisms are associated with the tumor progression and metastasis. MicroRNAs (miRNAs) are a class of non-coding RNAs (ncRNAs) family that has important functions in regulation of the cellular processes such as cell proliferation, apoptosis, and tumor progression. Moreover, they have higher stability in body fluids compared with mRNAs which can be introduced as non-invasive diagnostic markers in cancer patients. MiR-132 has important functions as tumor suppressor or oncogene in different cancers. In the present review, we have summarized all of the studies which have been reported the role of miR-132 during tumor progressions. We categorized the miR-132 target genes based on their cell and molecular functions. Although, it has been reported that the miR-132 mainly functions as a tumor suppressor, it has also oncogenic functions especially in pancreatic tumors. MiR-132 mainly exerts its roles during tumor progressions by regulation of the transcription factors and signaling pathways. Present review clarifies the tumor specific molecular mechanisms of miR-132 to introduce that as an efficient non-invasive diagnostic marker in various cancers.

Role of tyrosine kinases in bladder cancer progression: an overview.

BACKGROUND: Bladder cancer (BCa) is a frequent urothelial malignancy with a high ratio of morbidity and mortality. Various genetic and environmental factors are involved in BCa progression. Since, majority of BCa cases are diagnosed after macroscopic clinical symptoms, it is required to find efficient markers for the early detection. Receptor tyrosine-kinases (RTKs) and non-receptor tyrosine-kinases (nRTKs) have pivotal roles in various cellular processes such as growth, migration, differentiation, and metabolism through different signaling pathways. Tyrosine-kinase deregulations are observed during tumor progressions via mutations, amplification, and chromosomal abnormalities which introduces these factors as important candidates of anti-cancer therapies. MAIN BODY: For the first time in present review we have summarized all of the reported tyrosine-kinases which have been significantly associated with the clinicopathological features of BCa patients. CONCLUSIONS: This review highlights the importance of tyrosine-kinases as critical markers in early detection and therapeutic purposes among BCa patients and clarifies the molecular biology of tyrosine-kinases during BCa progression and metastasis. Video abstract.

MicroRNA-135b mainly functions as an oncogene during tumor progression.

Late diagnosis is considered one of the main reasons of high mortality rate among cancer patients that results in therapeutic failure and tumor relapse. Therefore, it is needed to evaluate the molecular mechanisms associated with tumor progression to introduce efficient markers for the early tumor detection among cancer patients. The remarkable stability of microRNAs (miRNAs) in body fluids makes them potential candidates to use as the non-invasive tumor biomarkers in cancer screening programs. MiR-135b has key roles in prognosis and survival of cancer patients by either stimulating or inhibiting cell proliferation, invasion, and angiogenesis. Therefore, in the present review we assessed the molecular biology of miR-135b during tumor progression to introduce that as a novel tumor marker in cancer patients. It has been reported that miR-135b mainly acts as an oncogene by regulation of transcription factors, signaling pathways, drug response, cellular metabolism, and autophagy. This review paves the way to suggest miR-135b as a tumor marker and therapeutic target in cancer patients following the further clinical trials and animal studies.

MicroRNAs as the critical regulators of Forkhead box protein family during gynecological and breast tumor progression and metastasis.

Gynecological and breast tumors are one of the main causes of cancer-related mortalities among women. Despite recent advances in diagnostic and therapeutic methods, tumor relapse is observed in a high percentage of these patients due to the treatment failure. Late diagnosis in advanced tumor stages is one of the main reasons for the treatment failure and recurrence in these tumors. Therefore, it is necessary to assess the molecular mechanisms involved in progression of these tumors to introduce the efficient early diagnostic markers. Fokhead Box (FOX) is a family of transcription factors with a key role in regulation of a wide variety of cellular mechanisms. Deregulation of FOX proteins has been observed in different cancers. MicroRNAs (miRNAs) as a group of non-coding RNAs have important roles in post-transcriptional regulation of the genes involved in cellular mechanisms. They are also the non-invasive diagnostic markers due to their high stability in body fluids. Considering the importance of FOX proteins in the progression of breast and gynecological tumors, we investigated the role of miRNAs in regulation of the FOX proteins in these tumors. MicroRNAs were mainly involved in progression of these tumors through FOXM, FOXP, and FOXO. The present review paves the way to suggest a non-invasive diagnostic panel marker based on the miRNAs/FOX axis in breast and gynecological cancers.

MicroRNA-495: a therapeutic and diagnostic tumor marker.

Therapeutic and diagnostic progresses have significantly reduced the mortality rate among cancer patients during the last decade. However, there is still a high rate of mortality among cancer patients. One of the important reasons involved in the high mortality rate is the late diagnosis in advanced tumor stages that causes the failure of therapeutic strategies in these patients. Therefore, investigating the molecular mechanisms involved in tumor progression has an important role in introducing the efficient early detection markers. MicroRNAs (miRNAs) as stable factors in body fluids are always considered as non-invasive diagnostic and prognostic markers. In the present review, we investigated the role of miR-495 in tumor progression. It has been reported that miR-495 has mainly a tumor suppressor function through the regulation of transcription factors and tyrosine kinases as well as cellular processes such as multidrug resistance, chromatin remodeling, and signaling pathways. This review can be an effective step towards introducing the miR-495 as a non-invasive diagnostic/prognostic marker as well as a suitable target in tumor therapy.

Molecular biology of microRNA-342 during tumor progression and invasion.

Cancer is considered as one of the main causes of human deaths and health challenges in the world. Various factors are involved in the high death rate of cancer patients, including late diagnosis and drug resistance that result in treatment failure and tumor recurrence. Invasive diagnostic methods are one of the main reasons of late tumor detection in cancer patients. Therefore, it is necessary to investigate the molecular tumor biology to introduce efficient non-invasive markers. MicroRNAs (miRNAs) are involved in regulation of the cellular mechanisms such as cell proliferation, apoptosis, and migration. MiRNAs deregulations have been also frequently shown in different tumor types. Here, we discussed the molecular mechanisms of miR-342 during tumor growth. MiR-342 mainly functions as a tumor suppressor by the regulation of transcription factors and signaling pathways such as WNT, PI3K/AKT, NF-kB, and MAPK. Therefore, miR-342 mimics can be used as a reliable therapeutic strategy to inhibit the tumor cells growth. The present review can also pave the way to introduce the miR-342 as a non-invasive diagnostic/prognostic marker in cancer patients.

MicroRNA-377: A therapeutic and diagnostic tumor marker.

Cancer is considered as one of the main causes of human deaths globally. Despite the recent progresses in therapeutic modalities, there is still a high rate of mortality among cancer patients. Late diagnosis in advanced tumor stages is one of the main reasons for treatment failure in cancer patients. Therefore, it is required to suggest the novel strategies for the early tumor detection. MicroRNAs (miRNAs) have critical roles in neoplastic transformation by regulation of cell proliferation, migration, and apoptosis. They are always considered as non-invasive markers due to their high stability in body fluids. Since, all of the miRNAs have tissue-specific functions in different tumors as tumor suppressor or oncogene; it is required to investigate the molecular mechanisms of every miRNA in different tumors to introduce that as a suitable non-invasive diagnostic marker in cancer patients. For the first time in the present review, we discussed the role of miR-377 during tumor progression. It has been reported that miR-377 mainly functions as a tumor suppressor through the regulation of signaling pathways and transcription factors. This review is an important step toward introducing the miR-377 as a novel diagnostic marker as well as a therapeutic target in cancer patients.

MicroRNA-506 as a tumor suppressor in anaplastic thyroid carcinoma by regulation of WNT and NOTCH signaling pathways.

Objectives: Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid tumor type that has a poor prognosis due to its high therapeutic resistance. Since ATC accounts for half of thyroid cancer-related deaths, it is required to introduce novel therapeutic targets to increase survival in ATC patients. WNT and NOTCH signaling pathways are the pivotal regulators of cell proliferation and migration that can be regulated by microRNAs. We assessed the role of miR-506 in the regulation of cell migration, apoptosis, and drug resistance via NOTCH and WNT pathways in ATC cells. Materials and Methods: The levels of miR-506 expressions were assessed in ATC cells and tissues. The levels of NOTCH, WNT, and EMT-related gene expressions were also assessed in miR-506 ectopic expressed cells compared with controls. Cell migration and drug resistance were also evaluated to assess the role of miR-506 in the regulation of ATC aggressiveness. Results: There were significant miR-506 down-regulations in ATC cells and clinical samples compared with normal cells and margins. MiR-506 suppressed NOTCH and WNT signaling pathways through LEF1, DVL, FZD1, HEY2, HES5, and HEY2 down-regulations, and APC and GSK3b up-regulations. MiR-506 significantly inhibited ATC cell migration and EMT (P=0.028). Moreover, miR-506 significantly increased Cisplatin (P=0.004), Paclitaxel (P<0.0001), and Doxorubicin (P=0.0014) sensitivities in ATC cells. Conclusion: MiR-506 regulated EMT, cell migration, and chemoresistance through regulation of WNT and NOTCH signaling pathways in ATC cells. Therefore, after confirmation with animal studies, it can be introduced as an efficient novel therapeutic factor for ATC tumors.

Curcumin Combats against Gastrointestinal Cancer: A Review of Current Knowledge Regarding Epigenetics Mechanisms with a Focus on DNA Methylation.

Gastrointestinal (GI) cancers are one of the most common human malignancies and a leading cause of morbidity and mortality worldwide. One of the most prominent hallmarks of cancer and a basic trait of almost all GI malignancies is genomic/epigenomics alterations. DNA methylation is highlighted as a fundamental mechanism underlying the inactivation of several tumor-suppressor gene signaling pathways. Thus, sites of DNA methylation can be triggered for cancer therapy. Available therapeutic procedures for GI cancer show unsatisfactory efficacy, and some treatments are associated with severe side effects, including ulceration or bleeding. Therefore, it is essential to find alternative treatments. There is growing evidence indicating that some chemopreventive phytochemicals can combat cancer. One of the most systematically investigated nutraceuticals for its advantages in managing different diseases is curcumin (CUR). CUR is well known for its potent anticancer characteristics by targeting epigenetic mechanisms, with DNA methylation at the forefront. Prior investigations have indicated that CUR treatment can benefit GI cancers by controlling several signaling pathways related to oxidative stress and epigenomics pathways. The present literature displays recent evidence regarding DNA methylation alterations by CUR and its potential role in GI cancer prevention and treatment.

MicroRNAs as the critical regulators of cell migration and invasion in thyroid cancer.

Thyroid cancer (TC) is one of the most frequent endocrine malignancies that is more common among females. Tumor recurrence is one of the most important clinical manifestations in differentiated TC which is associated with different factors including age, tumor size, and histological features. Various molecular processes such as genetic or epigenetic modifications and non-coding RNAs are also involved in TC progression and metastasis. The epithelial-to-mesenchymal transition (EMT) is an important biological process during tumor invasion and migration that affects the initiation and transformation of early-stage tumors into invasive malignancies. A combination of transcription factors, growth factors, signaling pathways, and epigenetic regulations affect the thyroid cell migration and EMT process. MicroRNAs (miRNAs) are important molecular factors involved in tumor metastasis by regulation of EMT-activating signaling pathways. Various miRNAs are involved in the signaling pathways associated with TC metastasis which can be used as diagnostic and therapeutic biomarkers. Since, the miRNAs are sensitive, specific, and non-invasive, they can be suggested as efficient and optimal biomarkers of tumor invasion and metastasis. In the present review, we have summarized all of the miRNAs which have been significantly involved in thyroid tumor cells migration and invasion. We also categorized all of the reported miRNAs based on their cellular processes to clarify the molecular role of miRNAs during thyroid tumor cell migration and invasion. This review paves the way of introducing a non-invasive diagnostic and prognostic panel of miRNAs in aggressive and metastatic TC patients.

MicroRNA-217: a therapeutic and diagnostic tumor marker.

INTRODUCTION: Cancer as one of the most common causes of death has always been one of the major health challenges globally. Since, the identification of tumors in the early tumor stages can significantly reduce mortality rates; it is required to introduce novel early detection tumor markers. MicroRNAs (miRNAs) have pivotal roles in regulation of cell proliferation, migration, apoptosis, and tumor progression. Moreover, due to the higher stability of miRNAs than mRNAs in body fluids, they can be considered as non-invasive diagnostic or prognostic markers in cancer patients. AREAS COVERED: In the present review we have summarized the role of miR-217 during tumor progressions. The miR-217 functions were categorized based on its target molecular mechanisms and signaling pathways. EXPERT OPINION: It was observed that miR-217 mainly exerts its function by regulation of the transcription factors during tumor progressions. The WNT, MAPK, and PI3K/AKT signaling pathways were also important molecular targets of miR-217 in different cancers. The present review clarifies the molecular biology of miR-217 and paves the way of introducing miR-217 as a non-invasive diagnostic marker and therapeutic target in cancer therapy.

MicroRNAs as the critical regulators of cisplatin resistance in gastric tumor cells.

Combined chemotherapeutic treatment is the method of choice for advanced and metastatic gastric tumors. However, resistance to chemotherapeutic agents is one of the main challenges for the efficient gastric cancer (GC) treatment. Cisplatin (CDDP) is used as an important regimen of chemotherapy for GC which induces cytotoxicity by interfering with DNA replication in cancer cells and inducing their apoptosis. Majority of patients experience cisplatin-resistance which is correlated with tumor metastasis and relapse. Moreover, prolonged and high-dose cisplatin administrations cause serious side effects such as nephrotoxicity, ototoxicity, and anemia. Since, there is a high rate of recurrence after CDDP treatment in GC patients; it is required to clarify the molecular mechanisms associated with CDDP resistance to introduce novel therapeutic methods. There are various cell and molecular processes associated with multidrug resistance (MDR) including drug efflux, detoxification, DNA repair ability, apoptosis alteration, signaling pathways, and epithelial-mesenchymal transition (EMT). MicroRNAs are a class of endogenous non-coding RNAs involved in chemo resistance of GC cells through regulation of all of the MDR mechanisms. In present review we have summarized all of the miRNAs associated with cisplatin resistance based on their target genes and molecular mechanisms in gastric tumor cells. This review paves the way of introducing a miRNA-based panel of prognostic markers to improve the efficacy of chemotherapy and clinical outcomes in GC patients. It was observed that miRNAs are mainly involved in cisplatin response of gastric tumor cells via regulation of signaling pathways, autophagy, and apoptosis.

Chemokines as the critical factors during bladder cancer progression: an overview.

Bladder cancer (BCa) is one of the most frequent urogenital malignancies which is mainly observed among men. There are various genetic and environmental risk factors associated with BCa progression. Transurethral endoscopic resection and open ablative surgery are the main treatment options for muscle invasive BCa. BCG therapy is also employed following the endoscopic resection to prevent tumor relapse. The tumor microenvironment is the main interaction site of tumor cells and immune system in which the immune cells are recruited via chemokines and chemokine receptors. In present review we summarized the main chemokines and chemokine receptors which have been associated with histopathological features of BCa patients in the world. This review highlights the chemokines and chemokine receptors as critical markers in early detection and therapeutic purposes among BCa patients and clarifies their molecular functions during BCa progression and metastasis.