Role of long non-coding RNAs and TGF-ß signaling in the regulation of breast cancer pathogenesis and therapeutic targets.

The cytokine known as transforming growth factor (TGF) is essential for cell development, differentiation, and apoptosis in BC. TGF-ß dysregulation can either promote or inhibit tumor development, and it is a key signaling pathway in BC spread. A recently identified family of ncRNAs known as lncRNAs has received a great deal of effort and is an important regulator of many cellular processes, including transcription of genes, chromatin remodeling, progression of the cell cycle, and posttranscriptional processing. Furthermore, both TGF-ß signaling and lncRNAs serve as important early-stage biomarkers for BC diagnosis and prognosis and also play a significant role in BC drug resistance. According to recent studies, lncRNAs can regulate TGF-ß by modulating its cofactors in BC. However, the particular functions of lncRNAs and the TGF-ß pathway in controlling BC progression are not well understood yet. This review explores the lncRNAs' functional properties in BC as tumor suppressors or oncogenes in the regulation of genes, with a focus on dysregulated TGF-ß signaling. Further, we emphasize the functional roles of lncRNAs and TGF-ß pathway in the progression of BC to discover new treatment strategies and better comprehend the fundamental cellular pathways.

Current landscape of miRNAs and TGF-ß signaling in lung cancer progression and therapeutic targets.

Lung cancer (LC) is the primary reason for cancer-associated fatalities globally. Due to both tumor-suppressing and tumor-promoting activities, the TGF-ß family of growth factors is extremely essential to tumorigenesis. A non-coding single-stranded short RNA called microRNA (miRNA), which is made up of about 22 nt and is encoded by endogenous genes, can control normal and pathological pathways in various kinds of cancer, including LC. Recent research demonstrated that the TGF-ß signaling directly can affect the synthesis of miRNAs through suppressor of mothers against decapentaplegic (SMAD)-dependent activity or other unidentified pathways, which could generate allostatic feedback as a result of TGF-ß signaling stimulation and ultimately affect the destiny of cancer tissues. In this review, we emphasize the critical functions of miRNAs in lung cancer progression and, more critically, how they affect the TGF-ß signaling pathway, and explore the role of both the TGF-ß signaling pathway and miRNAs as potential therapeutic targets for improving the treatments of LC patients.

Molecular study of colorectal carcinoma and EGFR gene mutations.

The development of various human tumors can be related to the activation of the Epidermal growth factor receptor (EGFR) and its subsequent signaling pathways. There are so much alertness and awareness that has been given to the EGFR pathway recently because EGFR and some downstream components together render as targets for anticancer therapy. The EGFR pathway and its impact on colorectal carcinogenesis and assessments are the assertiveness in this paper. In this study, we took 1034 patients with colorectal carcinoma that were recorded as a medical survey we used a standard questionnaire for those patients and we used real time PCR for 30 patients from 134 cases that have colorectal carcinoma to detect if there is any mutation in the EGFR gene. We chose 4 exons for that purpose which were exons (18),(19),(20) and (21) of the EGFR gene. After deparaffinization and DNA extraction from the tissues of patients with colorectal carcinoma, we used real-time PCR technique by using (Rotor gene) kit and we were run our samples with the control group of the same patients and internal control from the kit to compare if there was any mutation but there was not any mutation in those exons of our (30) samples of paraffin-embedded (FFPE) tissues.

Strategies to overcome the main challenges of the use of exosomes as drug carrier for cancer therapy.

Exosomes are naturally occurring nanosized particles that aid intercellular communication by transmitting biological information between cells. Exosomes have therapeutic efficacy that can transfer their contents between cells as natural carriers. In addition, the exosomal contents delivered to the recipient pathological cells significantly inhibit cancer progression. However, exosome-based tumor treatments are inadequately precise or successful, and various challenges should be adequately overcome. Here, we discuss the significant challenges that exosomes face as drug carriers used for therapeutic targets and strategies for overcoming these challenges in order to promote this new incoming drug carrier further and improve future clinical outcomes. We also present techniques for overcoming these challenges.

Functional interplay between long non-coding RNAs and Breast CSCs.

Breast cancer (BC) represents aggressive cancer affecting most women's lives globally. Metastasis and recurrence are the two most common factors in a breast cancer patient's poor prognosis. Cancer stem cells (CSCs) are tumor cells that are able to self-renew and differentiate, which is a significant factor in metastasis and recurrence of cancer. Long non-coding RNAs (lncRNAs) describe a group of RNAs that are longer than 200 nucleotides and do not have the ability to code for proteins. Some of these lncRNAs can be mainly produced in various tissues and tumor forms. In the development and spread of malignancies, lncRNAs have a significant role in influencing multiple signaling pathways positively or negatively, making them promise useful diagnostic and prognostic markers in treating the disease and guiding clinical therapy. However, it is not well known how the interaction of lncRNAs with CSCs will affect cancer development and progression.Here, in this review, we attempt to summarize recent findings that focus on lncRNAs affect cancer stem cell self-renewal and differentiation in breast cancer development and progression, as well as the strategies and challenges for overcoming lncRNA's therapeutic resistance.

The role of HPV gene expression and selected cellular MiRNAs in lung cancer development.

BACKGROUND: The high mortality rate of lung cancer can be justified that strong need to explore new aspect of tumor biology. Human papillomavirus (HPV) has been detected as risk factor for the development of lung cancer. The aim of this study was to determine the role of HPV and cellular/miRNAs genes expression in the epithelial-mesenchymal transition (EMT) and development of lung cancer. METHODS: In this case-control study, 109 lung cancer tissue and 52 controls were included. We analyzed the presence of HPV infection, its genotypes (in positive samples) and the expression of viral genes (E2, E6 and E7). Also, We examined the expression of celluar factors including (a) p53 and retinoblastoma (Rb) (as anti-carcinogenic genes), (b) EMT related genes, (c) selected miRNAs. RESULTS: Our results reported 51.4% and 23.1% of HPV genome in tumor tissues and control tissues samples, respectively. There was a significant association between the HPV positive status and lung cancer (OR = 3.26, 95% C.I = 1.47-7.02, P = 0.001). HPV type 16 was the most prevalent genotype in tissues. The expression of p53, RB, TIMP1, CCNG-1, E-cad and PTPN13 were decreased while MMP-2 and N-cad were increased in HPV-positive tumor/control tissues compared to HPV-negative tissues. Also, among miRNAs, let-7, miR-23, miR-34, miR-125, miR-146 were downregulated and miR-20, miR-424 were upregulated in HPV-positve tissues compared to HPV-negative tissues. CONCLUSION: This study demonstrated that HPV infection and interaction with cellular genes and miRNAs promote EMT which involved in the lung cancer development.

Down-regulation of Survivin and Bcl-2 concomitant with the activation of caspase-3 as a mechanism of apoptotic death in KG1a and K562 cells upon exposure to a derivative from ciprofloxacin family.

Ciprofloxacin derivatives belong to a family of antibiotics called fluoroquinolones. Recently, these compounds have been recommended for the treatment of cancer. In the present study, we assessed the cytotoxicity of several new synthetic ciprofloxacin derivatives and the apoptosis-inducing activity of the most efficient derivative in two human myeloid leukemia K562 and KG1-a cell lines. Among the prepared ciprofloxacin derivatives, 1-cyclopropyl-7-(4-(2-((3,7-dimethyloct-6-en-1-yl)oxy)-2-oxoethyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4dihydroquinoline-3-carboxylic acid (4-DMOCP) was more active compound with IC50 of 19.56 and 22.13 µM for K562 and KG1-a, respectively. Apoptotic activity of the 4-DMOCP was examined morphologically through Hoechst 33258 staining, Annexin V/PI double staining, and caspase-3 activity assays. Changes in the expression level of some apoptosis-related genes and protein, including Bcl-2, Bax, Survivin, p53, Caspase-8 and Caspase-9 were evaluated by the real-time quantitative PCR (qRT PCR) and western blotting. The qRT PCR analysis showed that 4-DMOCP induces apoptosis in both cell lines via the down-regulation of Survivin and Bcl2, up-regulation of caspase-8 and -9, as well as a time-dependent increase in the Bax/Bcl2 transcripts. The mRNA level of p53 was also increased in both cell lines. In addition, western blot analysis revealed that treatment with the compound, down-regulated the protein expression levels of Bcl2 and Survivin and up-regulated the protein level of Bax in both cell lines. These findings suggest that these new compounds can be good candidates for the treatment of acute and chronic myeloid leukemia.

Exosomal non-coding RNAs: Blueprint in colorectal cancer metastasis and therapeutic targets.

Colorectal cancer (CRC) is ranked as the world's third-most prevalent cancer, and metastatic CRC considerably increases cancer-related fatalities globally. A number of complex mechanisms that are strictly controlled at the molecular level are involved in metastasis, which is the primary reason for death in people with CRC. Recently, it has become clear that exosomes, which are small extracellular vesicles released by non-tumorous and tumorigenic cells, play a critical role as communication mediators among tumor microenvironment (TME). To facilitate communication between the TME and cancer cells, non-coding RNAs (ncRNAs) play a crucial role and are recognized as potent regulators of gene expression and cellular processes, such as metastasis and drug resistance. NcRNAs are now recognized as potent regulators of gene expression and many hallmarks of cancer, including metastasis. Exosomal ncRNAs, like miRNAs, circRNAs, and lncRNAs, have been demonstrated to influence a number of cellular mechanisms that contribute to CRC metastasis. However, the molecular mechanisms that link exosomal ncRNAs with CRC metastasis are not well understood. This review highlights the essential roles that exosomal ncRNAs play in the progression of CRC metastatic disease and explores the therapeutic choices that are open to patients who have CRC metastases. However, exosomal ncRNA treatment strategy development is still in its early phases; consequently, additional investigation is required to improve delivery methods and find novel therapeutic targets as well as confirm the effectiveness and safety of these therapies in preclinical and clinical contexts.

Expression analysis of cell cycle related lncRNAs in breast cancer tissues.

Cell cycle regulation is an important cellular function. Abnormal regulation of this process can cause cancer. Several genes are involved in this process. There is no comprehensive study on expression pattern of cell cycle related lncRNAs in breast cancer patients. In the current study, we evaluated expressions of LINC00668, PRDM16-DT, SNHG7 and CDKN2A in 42 pairs of breast cancer tissues and adjacent non-tumoral tissues. Expression of SNHG7 was significantly lower in tumoral tissues compared with non-tumoral tissues. However, expressions of LINC00668, PRDM16-DT and CDKN2A were not significantly different between these two sets of samples. Expression levels of SNHG7 could separate tumoral tissues from non-tumoral tissues with AUC value= 0.66, sensitivity= 61% and specificity= 73%. Expression of CDKN2A was associated with clinical stage (P value=0.01). Expression levels of LINC00668, PRDM16-DT, SNHG7 and CDKN2A were higher in estrogen receptor (ER) positive samples compared with ER negative ones (P values=0.044, 0.008, 0.002 and 0.022, respectively). Moreover, expression of SNHG7 was higher in progesterone receptor (PR) positive samples compared with PR negative ones (P value=0.02). Finally, expressions of PRDM16-DT, SNHG7 and CDKN2A were higher in HER2/neu positive samples compared with HER2/neu negative ones (P values=0.017, 0.02 and 0.021, respectively). Taken together, our study demonstrates possible roles of these genes in breast cancer and warrants further functional studies.

Targeting miRNA by CRISPR/Cas in cancer: advantages and challenges.

Clustered regulatory interspaced short palindromic repeats (CRISPR) has changed biomedical research and provided entirely new models to analyze every aspect of biomedical sciences during the last decade. In the study of cancer, the CRISPR/CRISPR-associated protein (Cas) system opens new avenues into issues that were once unknown in our knowledge of the noncoding genome, tumor heterogeneity, and precision medicines. CRISPR/Cas-based gene-editing technology now allows for the precise and permanent targeting of mutations and provides an opportunity to target small non-coding RNAs such as microRNAs (miRNAs). However, the development of effective and safe cancer gene editing therapy is highly dependent on proper design to be innocuous to normal cells and prevent introducing other abnormalities. This study aims to highlight the cutting-edge approaches in cancer-gene editing therapy based on the CRISPR/Cas technology to target miRNAs in cancer therapy. Furthermore, we highlight the potential challenges in CRISPR/Cas-mediated miRNA gene editing and offer advanced strategies to overcome them.

Exosomal circular RNAs: New player in breast cancer progression and therapeutic targets.

Breast cancer is the most prevalent type of malignancy among women. Exosomes are extracellular vesicles of cell membrane origin that are released via exocytosis. Their cargo contains lipids, proteins, DNA, and different forms of RNA, including circular RNAs. Circular RNAs are new class of non-coding RNAs with a closed-loop shape involved in several types of cancer, including breast cancer. Exosomes contained a lot of circRNAs which are called exosomal circRNAs. By interfering with several biological pathways, exosomal circRNAs can have either a proliferative or suppressive role in cancer. The involvement of exosomal circRNAs in breast cancer has been studied with consideration to tumor development and progression as well as its effects on therapeutic resistance. However, its exact mechanism is still unclear, and there have not been available clinical implications of exo-circRNAs in breast cancer. Here, we highlight the role of exosomal circRNAs in breast cancer progression and to highlight the most recent development and potential of circRNAas therapeutic targets and diagnostics for breast cancer.

Identification of expression of CCND1-related lncRNAs in breast cancer.

Cyclin D1 has been shown to participate in the pathogenesis of breast cancer. This cell cycle-related protein has direct or indirect interactions with long non-coding RNAs (lncRNAs). In the present two-step study, we first identified CCND1-related lncRNAs through an in silico approach. Then, we measured expression of CCND1 mRNA and five lncRNAs in paired breast cancer samples and their matched non-cancerous samples obtained from adjacent tissues. HOTTIP expression was significantly higher in breast cancer tissues compared with adjacent tissues (expression ratio (95% CI)= 4.63 (1.56-13.76), P value= 0.0070). Similarly, CBR3-AS1 was up-regulated in cancerous tissues compared with control tissues (expression ration (95% CI)= 3.26 (1.35-7.86), P value= 0.0122). Expression of HOTTIP was higher in estrogen receptor (ER) negative samples compared with ER positive ones (-4.35 ± 1.33 versus -4.63 ± 0.62, P value=0.002). CBR3-AS1 could differentiate between these two sets of samples with AUC±SD, sensitivity, specificity and P values of 0.7 ± 0.05, 0.9, 0.49 and 0.003, respectively. These values were 0.68 ± 0.04, 0.87, 0.34 and 0.04 for HOTTIP. Although we could not find difference in expression of CCND1 between these two sets of samples, we reported up-regulation of two CCND1-related lncRNAs in breast cancer samples. These lncRNAs are putative markers for breast cancer.

The Role of Circular RNAs in the Carcinogenesis of Bladder Cancer.

Circular RNAs (circRNAs) are a group of transcripts with enclosed configurations which can regulate gene expression. These transcripts have important roles in normal development and in the pathogenesis of disorders. Recent evidence has supported involvement of circRNAs in the development of bladder cancer. Several circRNAs such as circ_0058063, hsa-circRNA-403658, circPDSS1, circCASC15, circRNA-MYLK, and circRNA_103809 have been upregulated in bladder cancer samples. On the other hand, hsa_circ_0137606, BCRC-3, circFUT8, hsa_circ_001598, circSLC8A1, hsa_circ_0077837, hsa_circ_0004826, and circACVR2A are among downregulated circRNAs in bladder cancer. Numerous circRNAs have diagnostic or prognostic value in bladder cancer. In this review, we aim to outline the latest findings about the role of circRNAs in bladder cancer and introduce circRNAs for further investigations as therapeutic targets.

Signaling pathways modulated by miRNAs in breast cancer angiogenesis and new therapeutics.

MicroRNAs (miRNAs) act as oncogenes or tumor suppressors by suppressing the expression of target genes, some of which are engaged in angiogenic signaling pathways directly or indirectly. Tumor development and metastasis are dependent on angiogenesis, and it is the main reason for the poor prognosis of cancer patients. New blood vessels are formed from pre-existing vessels when angiogenesis occurs. Thus, it is essential to develop primary tumors and the spread of cancer to surrounding tissues. MicroRNAs (miRNAs) are small noncoding RNAs involved in various biological processes. They can bind to the 3'-UTR of their target genes and prevent them from expressing. MiRNAs control the activity of endothelial cells (ECs) through altering many biological pathways, which plays a key role in cancer progression and angiogenesis. Recent findings revealed that tumor-derived extracellular vesicles participated directly in the control of tumor angiogenesis by delivering miRNAs to ECs. miRNAs recently show great promise in cancer therapies to inhibit angiogenesis. In this study, we showed the miRNA-regulated signaling pathways in tumor angiogenesis with highlighting the anti-angiogenic therapy response and miRNA delivery methods that have been used to inhibit angiogenesis in both in vivo and in vitro studies.

The emerging roles of NGS in clinical oncology and personalized medicine.

Next-generation sequencing (NGS) has been increasingly popular in genomics studies over the last decade, as new sequencing technology has been created and improved. Recently, NGS started to be used in clinical oncology to improve cancer therapy through diverse modalities ranging from finding novel and rare cancer mutations, discovering cancer mutation carriers to reaching specific therapeutic approaches known as personalized medicine (PM). PM has the potential to minimize medical expenses by shifting the current traditional medical approach of treating cancer and other diseases to an individualized preventive and predictive approach. Currently, NGS can speed up in the early diagnosis of diseases and discover pharmacogenetic markers that help in personalizing therapies. Despite the tremendous growth in our understanding of genetics, NGS holds the added advantage of providing more comprehensive picture of cancer landscape and uncovering cancer development pathways. In this review, we provided a complete overview of potential NGS applications in scientific and clinical oncology, with a particular emphasis on pharmacogenomics in the direction of precision medicine treatment options.

Long Non-coding RNA RMRP in the Pathogenesis of Human Disorders.

RNA component of mitochondrial RNA processing endoribonuclease (RMRP) is a non-coding transcript firstly acknowledged for its association with the cartilage-hair hypoplasia (CHH) syndrome, a rare autosomal recessive condition. This transcript has been spotted in both nucleus and mitochondria. In addition to its role in the pathogenesis of CHH, RMRP participates in the pathogenesis of cancers. Independent studies in bladder cancer, colon cancer, hepatocellular carcinoma, lung cancer, breast carcinoma and multiple myeloma have confirmed the oncogenic effects of RMRP. Mechanistically, RMRP serves as a sponge for some miRNAs such as miR-206, miR-613, and miR-217. In addition to these miRNAs, expressions of tens of miRNAs have been altered following RMRP silencing, implying the vast extent of RMRP/miRNA network. In the present narrative review, we explain the role of RMRP in the development of cancers and some other non-malignant disorders.

Role of lncRNA BANCR in Human Cancers: An Updated Review.

Being located in a gene desert region on 9q21.11-q21.12, BRAF-activated non-protein coding RNA (BANCR) is an lncRNA with 693 bp length. It has been discovered in 2012 in a research aimed at assessment of gene expression in the melanocytes in association with BRAF mutation. Increasing numbers of studies have determined its importance in the tumorigenesis through affecting cell proliferation, migration, invasion, apoptosis, and epithelial to mesenchymal transition. BANCR exerts its effects via modulating some tumor-related signaling pathways particularly MAPK and other regulatory mechanisms such as sponging miRNAs. BANCR has been up-regulated in endometrial, gastric, breast, melanoma, and retinoblastoma. Conversely, it has been down-regulated in some other cancers such as those originated from lung, bladder, and renal tissues. In some cancer types such as colorectal cancer, hepatocellular carcinoma and papillary thyroid carcinoma, there is no agreement about BANCR expression, necessitating the importance of additional functional studies in these tissues. In the present manuscript, we review the investigations related to BANCR expression changes in cancerous cell lines, clinical samples, and animal models of cancer. We also discuss the outcome of its deregulation in cancer progression, prognosis, and the underlying mechanisms of these observations.

The role of circular RNAs in the development of hepatocellular carcinoma.

Circular RNAs (circRNAs) are a group of regulatory non-coding transcripts, which partake in the pathobiology of hepatocellular carcinoma (HCC). Numerous micro-array based investigations have discovered aberrant expression of circRNAs in HCC samples in comparison with para-cancerous sections. Furthermore, a number of in vitro and in vivo experimentations have aimed at understanding the molecular pathways of circRNAs contribution in the evolution of HCC. CircRNAs have interplay with a number of transcription factors such as ZEB1 that possibly mediates the effects of these transcripts in the epithelial-mesenchymal transition. Moreover, circRNAs functionally interact with miRNAs. CircRNA_0000502/ miR-124, circ_0001955/ miR-145-5p, circ_0001955/ miR-516a-5p and hsa_circ_0001955/miR-145-5p are examples of such interactions in the context of HCC. CircRNAs not only predict the course of HCC, but also, they can differentiate HCC samples from non-malignant liver tissues. In this review article, we have provided an inclusive summary of researches that quantified circRNAs profile in HCC. We also provide evidence for application of circRNAs as HCC biomarkers.

NF-KappaB interacting LncRNA: Review of its roles in neoplastic and non-neoplastic conditions.

NF-κB Interacting LncRNA (NKILA) is a long non-coding RNA (lncRNA) which has inhibitory roles on NF-κB. NF-κB regulates expression of several molecules participating in various crucial physiological reaction including immune responses, cell proliferation and differentiation, as well as cell death. Therefore, NKILA can be involved in the pathogenesis of a wide spectrum of human disorders. Numerous studies in hepatocellular carcinoma, breast cancer, melanoma, glioma and other types of neoplasms have indicated the role of NKILA in blockage of tumor growth and inhibition of metastasis. Further in vitro and in vivo assays including apoptosis assays, knock-down and knock-in experiments have verified such roles. In addition to its roles in neoplastic conditions, NKILA is involved in the pathogenesis of immune-related disorders. Dysregulation of expression of NKILA has been reported in patients with diverse conditions such as epilepsy, osteoarthritis, periodontitis and coronary artery disease. In this paper, we recapitulate the contribution of NKILA in neoplastic and non-neoplastic conditions.

A Diagnostic Panel for Acquired Immune-Mediated Polyneuropathies Based on the Expression of lncRNAs.

Long non-coding RNAs (lncRNAs) have been shown to alter immune responses, thus contributing to the pathobiology of autoimmune conditions. We investigated the expression levels of ANRIL, PICART1, MALAT1, CCAT1, CCAT2, and CCHE1 lncRNAs in acute and chronic inflammatory demyelinating polyneuropathy (AIDP and CIDP). ANRIL, PICART1, MALAT1, CCAT1, CCAT2, and CCHE1 lncRNAs were significantly downregulated in individuals with both AIDP and CIDP compared with unaffected individuals. Gender-based comparisons also verified such downregulations in both male and female subjects compared with sex-matched unaffected controls for all lncRNAs. There was no significant difference in the expression of any of the lncRNAs between cases with AIDP and cases with CIDP. While the expression levels of ANRIL and PICART1 were significantly correlated in healthy subjects (r = 0.86, p = 8.5E-16), similar analysis in cases with AIDP and CIDP revealed no significant correlation. The most robust correlation among patients was detected between ANRIL and MALAT1 lncRNAs (r = 0.59, p = 3.52E-6). ANRIL, MALAT1, and PICART1 had the diagnostic power of 0.96, 0.94, and 0.92 in distinguishing between cases with CIDP and controls, respectively. A combination of all lncRNAs resulted in 0.95 diagnostic power with a sensitivity of 0.85 and specificity of 0.96 for this purpose. Diagnostic power values of these lncRNAs in differentiation between cases with AIDP and controls were 0.98, 0.95, and 0.93, respectively. The combinatorial diagnostic power reached 0.98 for differentiation between cases with AIDP and controls. The six-lncRNA panel could differentiate combined cases with AIDP and CIDP from controls with area under the curve (AUC), sensitivity, and specificity values of 0.97, 0.90, and 0.96, respectively. Collectively, the lncRNA panel is suggested as a sensitive and specific diagnostic panel for acquired immune-mediated polyneuropathies.