miRNAs as short non-coding RNAs in regulating doxorubicin resistance.

The treatment of cancer patients has been prohibited by chemoresistance. Doxorubicin (DOX) is an anti-tumor compound disrupting proliferation and triggering cell cycle arrest via inhibiting activity of topoisomerase I and II. miRNAs are endogenous RNAs localized in cytoplasm to reduce gene level. Abnormal expression of miRNAs changes DOX cytotoxicity. Overexpression of tumor-promoting miRNAs induces DOX resistance, while tumor-suppressor miRNAs inhibit DOX resistance. The miRNA-mediated regulation of cell death and hallmarks of cancer can affect response to DOX chemotherapy in tumor cells. The transporters such as P-glycoprotein are regulated by miRNAs in DOX chemotherapy. Upstream mediators including lncRNAs and circRNAs target miRNAs in affecting capacity of DOX. The response to DOX chemotherapy can be facilitated after administration of agents that are mostly phytochemicals including curcumol, honokiol and ursolic acid. These agents can regulate miRNA expression increasing DOX's cytotoxicity. Since delivery of DOX alone or in combination with other drugs and genes can cause synergistic impact, the nanoparticles have been introduced for drug sensitivity. The non-coding RNAs determine the response of tumor cells to doxorubicin chemotherapy. microRNAs play a key role in this case and they can be sponged by lncRNAs and circRNAs, showing interaction among non-coding RNAs in the regulation of doxorubicin sensitivity.

siRNA and targeted delivery systems in breast cancer therapy

Recently, nucleic acid drugs have been considered as promising candidates in treatment of various diseases, especially cancer. Because of developing resistance to conventional chemotherapy, use of genetic tools in cancer therapy appears inevitable. siRNA is a RNAi tool with capacity of suppressing target gene. Owing to overexpression of oncogenic factors in cancer, siRNA can be used for suppressing those pathways. This review emphasizes the function of siRNA in treatment of breast tumor. The anti-apoptotic-related genes including Bcl-2, Bcl-xL and survivin can be down-regulated by siRNA in triggering cell death in breast cancer. STAT3, STAT8, Notch1, E2F3 and NF-κB are among the factors with overexpression in breast cancer that their silencing by siRNA paves the way for impairing tumor proliferation and invasion. The oncogenic mechanisms in drug resistance development in breast tumor such as lncRNAs can be suppressed by siRNA. Furthermore, siRNA reducing P-gp activity can increase drug internalization in tumor cells. Because of siRNA degradation at bloodstream and low accumulation at tumor site, nanoplatforms have been employed for siRNA delivery to suppress breast tumor progression via improving siRNA efficacy in gene silencing. Development of biocompatible and efficient nanostructures for siRNA delivery can make milestone progress in alleviation of breast cancer patients (AU)

Wnt/ß-catenin Signaling in Lung Cancer: Association with Proliferation, Metastasis, and Therapy Resistance.

The capacity of cancer cells for abnormal growth and metastasis has made it difficult to find a cure for tumor. Both males and females suffer from lung tumors, and physicians still deem them incurable. The initiation and development of lung tumors can be forced by genomic mutations. Wnt is a critical pathway for regulating growth, differentiation and migration. However, its oncogenic function has been observed in lung cancer. Wnt is able to increase the proliferation of lung tumors. The metastasis potential of lung tumors can be accelerated by Wnt/EMT axis. Overexpression of Wnt/ß-catenin prevents chemotherapy-mediated cell death in lung tumors. This pathway promotes cancer stem cell features in lung tumors which induce radioresistance. Anti-cancer agents, such as curcumin, are able to inhibit Wnt in lung tumor treatment. Wnt interaction with other factors in lung tumors is essential in controlling biological behavior, and non-coding RNA transcripts are the most well-known ones. It can be concluded from the current study that Wnt is an important regulator of lung tumorigenesis, and the translation of these findings into the clinic is vital.

The pharmacological and biological importance of EZH2 signaling in lung cancer.

Up to 18% of cancer-related deaths worldwide are attributed to lung tumor and global burden of this type of cancer is ascending. Different factors are responsible for development of lung cancer such as smoking, environmental factors and genetic mutations. EZH2 is a vital protein with catalytic activity and belongs to PCR2 family. EZH2 has been implicated in regulating gene expression by binding to promoter of targets. The importance of EZH2 in lung cancer is discussed in current manuscript. Activation of EZH2 significantly elevates the proliferation rate of lung cancer. Furthermore, metastasis and associated molecular mechanisms including EMT undergo activation by EZH2 in enhancing the lung cancer progression. The response of lung cancer to therapy can be significantly diminished due to EZH2 upregulation. Since EZH2 increases tumor progression, anti-cancer agents suppressing its expression reduce malignancy. In spite of significant effort in understanding modulatory function of EZH2 on other pathways, it appears that EZH2 can be also regulated and controlled by other factors that are described in current review. Therefore, translating current findings to clinic can improve treatment and management of lung cancer patients.

Paclitaxel and docetaxel resistance in prostate cancer: Molecular mechanisms and possible therapeutic strategies.

Prostate cancer is among most malignant tumors around the world and this urological tumor can be developed as result of genomic mutations and their accumulation during progression towards advanced stage. Due to lack of specific symptoms in early stages of prostate cancer, most cancer patients are diagnosed in advanced stages that tumor cells display low response to chemotherapy. Furthermore, genomic mutations in prostate cancer enhance the aggressiveness of tumor cells. Docetaxel and paclitaxel are suggested as well-known compounds for chemotherapy of prostate tumor and they possess a similar function in cancer therapy that is based on inhibiting depolymerization of microtubules, impairing balance of microtubules and subsequent delay in cell cycle progression. The aim of current review is to highlight mechanisms of paclitaxel and docetaxel resistance in prostate cancer. When oncogenic factors such as CD133 display upregulation and PTEN as tumor-suppressor shows decrease in expression, malignancy of prostate tumor cells enhances and they can induce drug resistance. Furthermore, phytochemicals as anti-tumor compounds have been utilized in suppressing chemoresistance in prostate cancer. Naringenin and lovastatin are among the anti-tumor compounds that have been used for impairing progression of prostate tumor and enhancing drug sensitivity. Moreover, nanostructures such as polymeric micelles and nanobubbles have been utilized in delivery of anti-tumor compounds and decreasing risk of chemoresistance development. These subjects are highlighted in current review to provide new insight for reversing drug resistance in prostate cancer.

siRNA and targeted delivery systems in breast cancer therapy.

Recently, nucleic acid drugs have been considered as promising candidates in treatment of various diseases, especially cancer. Because of developing resistance to conventional chemotherapy, use of genetic tools in cancer therapy appears inevitable. siRNA is a RNAi tool with capacity of suppressing target gene. Owing to overexpression of oncogenic factors in cancer, siRNA can be used for suppressing those pathways. This review emphasizes the function of siRNA in treatment of breast tumor. The anti-apoptotic-related genes including Bcl-2, Bcl-xL and survivin can be down-regulated by siRNA in triggering cell death in breast cancer. STAT3, STAT8, Notch1, E2F3 and NF-κB are among the factors with overexpression in breast cancer that their silencing by siRNA paves the way for impairing tumor proliferation and invasion. The oncogenic mechanisms in drug resistance development in breast tumor such as lncRNAs can be suppressed by siRNA. Furthermore, siRNA reducing P-gp activity can increase drug internalization in tumor cells. Because of siRNA degradation at bloodstream and low accumulation at tumor site, nanoplatforms have been employed for siRNA delivery to suppress breast tumor progression via improving siRNA efficacy in gene silencing. Development of biocompatible and efficient nanostructures for siRNA delivery can make milestone progress in alleviation of breast cancer patients.

Targeting PI3K/Akt signaling in prostate cancer therapy.

Urological cancers have obtained much attention in recent years due to their mortality and morbidity. The most common and malignant tumor of urological cancers is prostate cancer that imposes high socioeconomic costs on public life and androgen-deprivation therapy, surgery, and combination of chemotherapy and radiotherapy are employed in its treatment. PI3K/Akt signaling is an oncogenic pathway responsible for migration, proliferation and drug resistance in various cancers. In the present review, the role of PI3K/Akt signaling in prostate cancer progression is highlighted. The activation of PI3K/Akt signaling occurs in prostate cancer, while PTEN as inhibitor of PI3K/Akt shows down-regulation. Stimulation of PI3K/Akt signaling promotes survival of prostate tumor cells and prevents apoptosis. The cell cycle progression and proliferation rate of prostate tumor cells increase by PI3K/Akt signaling induction. PI3K/Akt signaling stimulates EMT and enhances metastasis of prostate tumor cells. Silencing PI3K/Akt signaling impairs growth and metastasis of prostate tumor cells. Activation of PI3K/Akt signaling mediates drug resistance and reduces radio-sensitivity of prostate tumor cells. Anti-tumor compounds suppress PI3K/Akt signaling in impairing prostate tumor progression. Furthermore, upstream regulators such as miRNAs, lncRNAs and circRNAs regulate PI3K/Akt signaling and it has clinical implications for prostate cancer patients.

Long non-coding RNA/epithelial-mesenchymal transition axis in human cancers: Tumorigenesis, chemoresistance, and radioresistance.

Epithelial-to-mesenchymal transition (EMT) is a process that involves the transformation of polarized epithelial cells to attain a mesenchymal phenotype that presents an elevated migratory potential, invasiveness, and antiapoptotic properties. Many studies have demonstrated that EMT is a prominent event that is associated with embryogenesis, tumor progression, metastasis, and therapeutic resistance. The EMT process is driven by key transcription factors (such as Snail, Twist, ZEB, and TGF-ß) and several long non-coding RNAs (lncRNAs) in many non-pathological as well as pathological conditions. In the present report, we have comprehensively discussed the oncogenic and tumor suppressor role of lncRNAs and their mechanism of action in the regulation of the EMT process in various cancers such as brain tumors, gastrointestinal tumors, and gynecological and urological tumors. We have also elaborated on the role of lncRNAs in the regulation of EMT-related transcription factors (such as Snail, Twist, ZEB, and TGF-ß) and therapeutic response (chemoresistance and radioresistance). Lastly, we have emphasized the role of exosomal lncRNAs in the regulation of EMT, metastasis, and therapeutic response in the aforementioned cancers. Taken together, this review provides a detailed insight into the understanding of role of lncRNAs/exosomal lncRNAs in EMT, metastasis, and therapeutic response in human cancers.

SOX2 function in cancers: Association with growth, invasion, stemness and therapy response.

Cancer is a leading cause of death worldwide and around 10 million deaths in 2020 were related to cancer. There are a number of therapeutic modalities for cancer such as chemotherapy, radiotherapy and surgery. However, tumor cells have capacity of developing resistance to chemotherapy and radiotherapy. Genetic mutations participate in development and progression of cancer. The current review focuses on the role of SOX2 transcription factor in cancer. SOX2 has capacity of increasing growth and metastasis of cancer cells. It functions as double-edged sword and has ability of suppressing tumor progression. Increasing evidence reveals that SOX2 is involved in triggering resistance to chemotherapy and radiotherapy. SOX2 promotes stemness of tumor cells and increases the number of cancer stem cells. SOX2 overexpression occurs in the tumor cells and tissues to ensure their proliferation and metastasis. Silencing SOX2 using CRISPR or siRNA impairs progression of the cancer cells and reduces their survival rate. SOX2 demonstrates interactions with other factors such as miRNAs, lncRNAs, STAT3 and Wnt/ß-catenin, among others to regulate progression of the tumor cells. SOX2 can be considered as a biomarker in cancer patients. SOX2 overexpression is associated with lymph node metastasis, low survival rate and poor prognosis of cancer patients.

LncRNA-miRNA axis in tumor progression and therapy response: An emphasis on molecular interactions and therapeutic interventions.

Epigenetic factors are critical regulators of biological and pathological mechanisms and they could interact with different molecular pathways. Targeting epigenetic factors has been an idea approach in disease therapy, especially cancer. Accumulating evidence has highlighted function of long non-coding RNAs (lncRNAs) as epigenetic factors in cancer initiation and development and has focused on their association with downstream targets. microRNAs (miRNAs) are the most well-known targets of lncRNAs and present review focuses on lncRNA-miRNA axis in malignancy and therapy resistance of tumors. LncRNA-miRNA regulates cell death mechanisms such as apoptosis and autophagy in cancers. This axis affects tumor metastasis via regulating EMT and MMPs. Besides, lncRNA-miRNA axis determines sensitivity of tumor cells to chemotherapy, radiotherapy and immunotherapy. Based on the studies, lncRNAs can be affected by drugs and genetic tools in cancer therapy and this may affect expression level of miRNAs as their downstream targets, leading to cancer suppression/progression. LncRNAs have both tumor-promoting and tumor-suppressor functions in cancer and this unique function of lncRNAs has complicated their implication in tumor therapy. LncRNA-miRNA axis can also affect other signaling networks in cancer such as PI3K/Akt, STAT3, Wnt/ß-catenin and EZH2 among others. Notably, lncRNA/miRNA axis can be considered as a signature for diagnosis and prognosis in cancers.

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.