ABSTRACT
The World Health Organisation recognised human papillomavirus (HPV) as the cause of multiple cancers, including head and neck cancers. HPV is a double-stranded DNA virus, and its viral gene expression can be controlled after infection by cellular and viral promoters. In cancer cells, the HPV genome is detected as either integrated into the host genome, episomal (extrachromosomal), or a mixture of integrated and episomal. Viral integration requires the breakage of both viral and host DNA, and the integration rate correlates with the level of DNA damage. Interestingly, patients with HPV-positive head and neck cancers generally have a good prognosis except for a group of patients with fully integrated HPV who show worst clinical outcomes. Those patients present with lowered expression of viral genes and limited infiltration of cytotoxic T cells. An impediment to effective therapy applications in the clinic is the sole testing for HPV positivity without considering the HPV integration status. This review will discuss HPV integration as a potential determinant of response to therapies in head and neck cancers and highlight to the field a novel therapeutic avenue that would reduce the cancer burden and improve patient survival.
Subject(s)
Head and Neck Neoplasms , Papillomavirus Infections , Humans , Head and Neck Neoplasms/virology , Head and Neck Neoplasms/therapy , Papillomavirus Infections/virology , Papillomavirus Infections/complications , Papillomaviridae/genetics , Virus IntegrationABSTRACT
Multiple myeloma (MM) is the second most prevalent hematologic malignancy. In the past few years, the survival of MM patients has increased due to the emergence of novel drugs and combination therapies. Nevertheless, one of the significant obstacles in treating most MM patients is drug resistance, especially for individuals who have experienced relapses or developed resistance to such cutting-edge treatments. One of the critical processes in developing drug resistance in MM is autophagic activity, an intracellular self-digestive process. Several possible strategies of autophagy involvement in the induction of MM-drug resistance have been demonstrated thus far. In multiple myeloma, it has been shown that High mobility group box protein 1 (HMGB1)-dependent autophagy can contribute to drug resistance. Moreover, activation of autophagy via proteasome suppression induces drug resistance. Additionally, the effectiveness of clarithromycin as a supplemental drug in treating MM has been reported recently, in which autophagy blockage is proposed as one of the potential action mechanisms of CAM. Thus, a promising therapeutic approach that targets autophagy to trigger the death of MM cells and improve drug susceptibility could be considered. In this review, autophagy has been addressed as a survival strategy crucial for drug resistance in MM.
Subject(s)
Multiple Myeloma , Humans , Multiple Myeloma/pathology , Cell Line, Tumor , Neoplasm Recurrence, Local , Drug Resistance, Neoplasm , AutophagyABSTRACT
BACKGROUND: Longitudinal epidemiological data are scarce examining the relationship between dietary patterns and respiratory outcomes in childhood. We investigated whether three distinct dietary patterns in mid-childhood were associated with lung function and incident asthma in adolescence. METHODS: In the Avon Longitudinal Study of Parents and Children, 'processed', 'traditional', and 'health-conscious' dietary patterns were identified using principal components analysis from food frequency questionnaires at 7 years of age. Post-bronchodilator forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory flow at 25-75% of FVC (FEF25-75) were measured at 15.5 years and were transformed to z-scores based on the Global Lung Function Initiative curves. Incident asthma was defined by new cases of doctor-diagnosed asthma at age 11 or 14 years. RESULTS: In multivariable-adjusted models, the 'health-conscious' pattern was positively associated with FEV1 (regression coefficient comparing top versus bottom quartile of pattern score 0.16, 95% CI 0.01 to 0.31, P for trend 0.04) and FVC (0.18, 95% CI 0.04 to 0.33, P for trend 0.02), while the 'processed' pattern was negatively associated with FVC (- 0.17, 95% CI - 0.33 to - 0.01, P for trend 0.03). Associations between the 'health-conscious' and 'processed' patterns and lung function were modified by SCGB1A1 and GPX4 gene polymorphisms. We found no evidence of an association between the 'traditional' pattern and lung function, nor between any pattern and FEF25-75 or incident asthma. CONCLUSIONS: A 'health-conscious' diet in mid-childhood was associated with higher subsequent lung function, while a diet high in processed food was associated with lower lung function.
Subject(s)
Asthma , Adolescent , Humans , Child , Longitudinal Studies , Asthma/diagnosis , Asthma/epidemiology , Diet/adverse effects , Vital Capacity , Forced Expiratory Volume , LungABSTRACT
Incomplete knowledge of the molecular basis of colorectal cancer, with subsequent limitations in early diagnosis and effective treatment, has contributed to this form of malignancy becoming the second most common cause of cancer-related death worldwide. With the advances in high-throughput profiling techniques and the availability of public data sets such as The Cancer Genome Atlas Program (TCGA), a broad range of coding transcripts have been profiled and their underlying modes of action have been mapped. However, there is still a huge gap in our understanding of noncoding RNA dysregulation. To this end, we used a bioinformatics approach to shortlist and evaluate yet-to be-profiled long noncoding RNAs (lncRNAs) in colorectal cancer. We analysed the TCGA RNA-seq data and followed this by validating the expression patterns using a qPCR technique. Analysing in-house clinical samples, the real-time PCR method revealed that the shortlisted lncRNAs, that is MER1 Repeat Containing Imprinted Transcript 1 (MIMT1) and Non-Protein Coding RNA 1550 (LINC01550), were down-regulated in colorectal cancer tumours compared with the paired adjacent normal tissues. Mechanistically, the in silico results suggest that LINC01550 could form a complex competitive endogenous RNA (ceRNA) network leading to the subsequent regulation of colorectal cancer-related genes, such as CUGBP Elav-Like Family Member (CELF2), Polypyrimidine Tract Binding Protein 1 (PTBP1) and ELAV Like RNA Binding Protein 1 (ELAV1). The findings of this work indicate that MIMT1 and LINC01550 could be novel tumour suppressor genes that can be studied further to assess their roles in regulating the cancer signalling pathway(s).
Subject(s)
Colorectal Neoplasms , MicroRNAs , RNA, Long Noncoding , Humans , Biomarkers, Tumor/genetics , CELF Proteins/genetics , CELF Proteins/metabolism , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Computational Biology , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Heterogeneous-Nuclear Ribonucleoproteins/metabolism , MicroRNAs/genetics , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Polypyrimidine Tract-Binding Protein/genetics , Polypyrimidine Tract-Binding Protein/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolismABSTRACT
The majority of human mRNAs generate alternative 3' untranslated regions (UTRs) through various processes, including RNA modifications such as RNA editing, m6A methylation, and alternative polyadenylation (APA), with 3'UTR splicing as an emerging mechanism. Multiple factors, ranging from the genome to transcriptome level, regulate these processes and contribute to 3'UTR heterogeneity. Genomic variants in 3'UTR regions as well as aberrant 3'UTR processing alter the transcriptomic landscape and are associated with cancer. Increasing evidence, aided by high-resolution sequencing technologies and large-scale computational analyses, points towards potential crosstalk between these processes, whose deregulation may further contribute to cancer pathogenesis. In-depth characterization of these events will increase our appreciation of their significance and help to drive therapeutic development in this field.
Subject(s)
Neoplasms , Humans , 3' Untranslated Regions/genetics , Neoplasms/genetics , Polyadenylation/genetics , RNA, Messenger/metabolism , TranscriptomeABSTRACT
In addition to genomic alterations, aberrant changes in post-transcriptional regulation can modify gene function and drive cancer development. RNA-binding proteins (RBPs) are a large class of post-transcriptional regulators that have been increasingly implicated in carcinogenesis. By integrating multi-omics data, we identify LARP1 as one of the most upregulated RBPs in colorectal cancer (CRC) and demonstrate its oncogenic properties. We perform LARP1:RNA interactome profiling and unveil a previously unexplored role for LARP1 in targeting the 3'UTR of oncogenes in CRC. Notably, we identify the proto-oncogenic transcription factor MYC as a key LARP1-regulated target. Our data show that LARP1 positively modulates MYC expression by associating with its 3'UTR. In addition, antisense oligonucleotide-mediated blocking of the interaction between LARP1 and the MYC 3'UTR reduces MYC expression and in vitro CRC growth. Furthermore, a systematic analysis of LARP1:protein interactions reveals IGF2BP3 and YBX1 as LARP1-interacting proteins that also regulate MYC expression and CRC development. Finally, we demonstrate that MYC reciprocally modulates LARP1 expression by targeting its enhancer. In summary, our data reveal a critical, previously uncharacterized role of LARP1 in promoting CRC tumorigenesis, validate its direct regulation of the proto-oncogene MYC and delineate a model of the positive feedback loop between MYC and LARP1 that promotes CRC growth and development.
Subject(s)
Autoantigens/metabolism , Carcinogenesis/metabolism , Colorectal Neoplasms/metabolism , Feedback, Physiological , Proto-Oncogene Proteins c-myc/metabolism , Ribonucleoproteins/metabolism , 3' Untranslated Regions , Animals , Autoantigens/genetics , Carcinogenesis/genetics , Cell Proliferation/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Mice , Oncogenes , Ribonucleoproteins/genetics , Transcriptome/genetics , Transfection , Tumor Burden/genetics , Xenograft Model Antitumor Assays , SS-B AntigenABSTRACT
Colorectal cancer is the 2nd leading cause of death in humans because of cancer. This rank of death could be due to the high rate of incidence from one hand, and the lack of sufficient diagnostic and therapeutic approaches from the other hand. Thus, molecular tools have been emerging as the potential biomarker to improve the early diagnosis and therapeutic management that subsequently could lead to the heightened survival rate of colorectal cancer patients. Long non-coding RNA (lncRNAs) have shown promising capabilities to be used in clinics. The profiling methods could identify novel aberrantly expressed lncRNAs in colorectal cancer. We, thus, performed a comprehensive and unbiased approach to shortlist the dysregulated lncRNAs based on the colon adenocarcinoma TCGA data. An unbiased in silico method was used to rank the yet to profiled lncRNAs in colorectal cancer. qPCR was used to measure the expression level of selected lncRNAs. Our results nominated ESRG, LINC00518, PWRN1, and TTTY14 lncRNAs as the top-hit novel lncRNAs with aberrant expression in colon cancer. The qPCR method was used to profile these lncRNAs that showed the up-regulation of ESRG and LINC00518, and down-regulation of TTTY14 in thirty paired colorectal cancer specimens. The statistical analyses demonstrated that ESRG, LINC00518 and PWRN1 could distinguish the tumor from normal samples. Moreover, ESRG showed a negative correlation with the overall survival of patients. These diagnostic and prognostic results suggest that profiling ESRG, LINC00518 and PWRN1 s may have implications in clinics.
Subject(s)
Colorectal Neoplasms , RNA, Long Noncoding/metabolism , Aged , Biomarkers, Tumor , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Medical Informatics , Middle Aged , PrognosisABSTRACT
3'UTR shortening in cancer has been shown to activate oncogenes, partly through the loss of microRNA-mediated repression. This suggests that many reported microRNA-oncogene target interactions may not be present in cancer cells. One of the most well-studied oncogenes is the transcription factor MYC, which is overexpressed in more than half of all cancers. MYC overexpression is not always accompanied by underlying genetic aberrations. In this study, we demonstrate that the MYC 3'UTR is shortened in colorectal cancer (CRC). Using unbiased computational and experimental approaches, we identify and validate microRNAs that target the MYC coding region. In particular, we show that miR-138 inhibits MYC expression and suppresses tumor growth of CRC and hepatocellular carcinoma (HCC) cell lines. Critically, the intravenous administration of miR-138 significantly impedes MYC-driven tumor growth in vivo. Taken together, our results highlight the previously uncharacterized shortening of the MYC 3'UTR in cancer, and identify miR-138 as a potent regulator of the heterogenous MYC transcript population.
Subject(s)
Carcinoma, HepatocellularABSTRACT
With nearly 10 million deaths, cancer is the leading cause of mortality worldwide. Along with major key parameters that control cancer treatment management, such as diagnosis, resistance to the classical and new chemotherapeutic reagents continues to be a significant problem. Intrinsic or acquired chemoresistance leads to cancer recurrence in many cases that eventually causes failure in the successful treatment and death of cancer patients. Various determinants, including tumor heterogeneity and tumor microenvironment, could cause chemoresistance through a diverse range of mechanisms. In this review, we summarize the key determinants and the underlying mechanisms by which chemoresistance appears. We then describe which strategies have been implemented and studied to combat such a lethal phenomenon in the management of cancer treatment, with emphasis on the need to improve the early diagnosis of cancer complemented by combination therapy.
Subject(s)
Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/physiology , Neoplasms/drug therapy , Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Humans , Neoplasms/metabolism , Neoplasms/pathology , Signal Transduction , Tumor Microenvironment/drug effects , Tumor Microenvironment/physiologyABSTRACT
Colorectal cancer is the main cause of human death due to cancer. This fact could be due to the insufficiency of early diagnosis or poor therapeutic strategies. Various molecular tools have been utilized in studies to assess their potentials as diagnostic biomarkers or determining factors in precision medicine. Among these molecules, long non-coding RNAs (lncRNA) have been emerging as accurate and potent transcripts to improve the detection of cancer. The overexpressed lncRNAs could also be deeply studied as the molecules for the targeted therapy in different malignancies, in particular colorectal cancer. Thus, we utilized an unbiased approach to select the up-regulated lncRNAs in colon adenocarcinoma via analyzing the TCGA dataset. Then, we validated the overexpression of two first-ranked lncRNAs, i.e., NPSR1-AS1 and TLX1NB, in our in-house colorectal cancer samples as compared to the paired adjacent normal tissues. The analyses revealed that these lncRNAs could significantly distinguish the tumor against the normal samples. The results may have implications in the early diagnosis and targeted therapy of colorectal cancer.
Subject(s)
Adenocarcinoma/diagnosis , Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Gene Expression/genetics , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Colorectal Neoplasms/therapy , Datasets as Topic , Early Detection of Cancer , Humans , Molecular Targeted TherapyABSTRACT
WBP2 is an emerging oncoprotein with diverse functions in breast tumorigenesis via regulating Wnt, epidermal growth factor receptor, estrogen receptor, and Hippo. Recently, evidence shows that WBP2 is tightly regulated by the components of the miRNA biogenesis machinery such as DGCR8 and Dicer via producing both WBP2's 3'UTR and coding DNA sequence-targeting miRNAs. This led us to hypothesize that WBP2 could provide a feedback loop to the biogenesis of its key upstream regulators by regulating the microprocessor complex activity. Indeed, WBP2 suppressed microprocessor activity by blocking the processing of pri-miRNAs to pre-miRNAs. WBP2 negatively regulated the assembly of the microprocessor complex via physical interactions with its components. Meta-analyses suggest that microprocessor complex components, in particular DGCR8, DDX5, and DEAD-Box Helicase17 (DDX17), have tumor-suppressive properties. 2D and 3D in vitro proliferation assays revealed that WBP2 blocked the tumor-suppressive properties of DGCR8, a key component of the microprocessor complex. In conclusion, WBP2 is a novel regulator of miRNA biogenesis that is a known dysregulated pathway in breast tumorigenesis. The reregulation of miRNA biogenesis machinery via targeting WBP2 protein may have implications in breast cancer therapy.
Subject(s)
Breast Neoplasms/genetics , MicroRNAs/biosynthesis , Trans-Activators/metabolism , Breast Neoplasms/metabolism , Carcinogenesis/genetics , Cell Line, Tumor , DEAD-box RNA Helicases/metabolism , Female , Humans , MicroRNAs/antagonists & inhibitors , RNA-Binding Proteins/metabolism , Ribonuclease III/metabolism , Trans-Activators/physiologyABSTRACT
Thyroid cancer is the most prevalent malignancy of the endocrine system and the ninth most common cancer globally. Despite the advances in the management of thyroid cancer, there are critical issues with the diagnosis and treatment of thyroid cancer that result in the poor overall survival of undifferentiated and metastatic thyroid cancer patients. Recent studies have revealed the role of different non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) that are dysregulated during thyroid cancer development or the acquisition of resistance to therapeutics, and may play key roles in treatment failure and poor prognosis of the thyroid cancer patients. Here, we systematically review the emerging roles and molecular mechanisms of ncRNAs that regulate thyroid tumorigenesis and drug response. We then propose the potential clinical implications of ncRNAs as novel diagnostic and prognostic biomarkers for thyroid cancer.
ABSTRACT
A higher expression of MALAT1 has been reported in breast cancer. However, more studies are needed to decipher the mechanisms by which this lncRNA imposes its oncogenic effects. In this study, blood and tissue samples were taken from healthy normal and breast cancer subjects. qPCR was used to analyze the gene expression. HRM-PCR method was carried out to genotype the selected samples. Computational analysis was recruited to find novel targets of MALAT1 and miR-143-3p. The data analyses revealed that MALAT1 was up-regulated in breast cancer and could be a distinctive factor to diagnose cancer. The expression of MALAT1 was inversely correlated with miR-143-3p expression in the studied clinical samples. The down-regulation of miR-143-3p was proven in the clinical tumor samples as compared to the healthy controls. A negative correlation of miR-143-3p with its putative target, RALGAPA2 was observed. A functional SNP rs3827693 located within the 3'UTR region of RALGAPA2 mRNA was validated in this study to associate with breast cancer risk. The rs3827693 allele G significantly decreased the breast cancer incidence and augmented the negative correlation between RALGAPA2 and miR-143-3p, presumably through strengthening the interaction between these two transcripts. This study proposed MALAT1 miR-143-3p and miR-143-3p RALGAPA2 axis in breast cancer, whereby the latter can be altered by the clinically functional SNP rs3827693.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , Epistasis, Genetic/genetics , GTPase-Activating Proteins/genetics , GTPase-Activating Proteins/metabolism , Gene Expression Regulation, Neoplastic/genetics , Gene Expression , MicroRNAs/genetics , MicroRNAs/metabolism , Polymorphism, Single Nucleotide , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Adult , Aged , Breast Neoplasms/metabolism , Female , Genotype , Humans , Middle Aged , Up-Regulation/geneticsABSTRACT
WBP2 transcription coactivator is an emerging oncoprotein and a key node of convergence between EGF and Wnt signaling pathways. Understanding how WBP2 is regulated has important implications for cancer therapy. WBP2 is tightly controlled by post-translational modifications, including phosphorylation and ubiquitination, leading to changes in subcellular localization, protein-protein interactions, and protein turnover. As the function of WBP2 is intricately linked to YAP and TAZ, we hypothesize that WBP2 is negatively regulated by the Hippo tumor suppressor pathway. Indeed, MST is demonstrated to negatively regulate WBP2 expression in a kinase-dependent but LATS-independent manner. This was observed in the majority of the breast cancer cell lines tested. The effect of MST was enhanced by SAV and concomitant with the inhibition of the transcription co-activation, in vitro and in vivo tumorigenesis activities of WBP2, resulting in good prognosis in xenografts. Downregulation of WBP2 by MST involved miRNA but not proteasomal or lysosomal degradation. Our data support the existence of a novel MST-Dicer signaling axis, which in turn regulates both WBP2 CDS- and UTR-targeting miRNAs expression, including miR-23a. MiR-23a targets the 3'UTR of WBP2 mRNA directly. Significant inverse relationships between WBP2 and MST or miR23a expression levels in clinical specimens were observed. In conclusion, WBP2 is a target of the Hippo/MST kinase; MST is identified as yet another rheostat in the regulation of WBP2 and its oncogenic function. The findings have implications in targeted therapeutics and precision medicine for breast cancer.
Subject(s)
Breast Neoplasms/metabolism , DEAD-box RNA Helicases/metabolism , Ribonuclease III/metabolism , Trans-Activators/metabolism , Adaptor Proteins, Signal Transducing/genetics , Cell Line, Tumor , DEAD-box RNA Helicases/genetics , Gene Expression/genetics , Gene Expression Regulation, Neoplastic/genetics , Hippo Signaling Pathway , Humans , MAP Kinase Kinase Kinases/metabolism , MAP Kinase Kinase Kinases/physiology , MCF-7 Cells , MicroRNAs/genetics , MicroRNAs/metabolism , Oncogene Proteins/genetics , Phosphorylation , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/physiology , Ribonuclease III/genetics , Signal Transduction/genetics , Trans-Activators/physiology , Transcription Factors/metabolism , Wnt Signaling PathwayABSTRACT
BACKGROUND: Gastric cancer is the fifth most common cancer worldwide. Along with environmental factors, such as Helicobacter pylori (H. pylori) infection, genetic changes play important roles in gastric tumor formations. miR-584 is a less well-characterized microRNA (miRNA), with apparent activity in human cancers. However, miR-584 expression pattern in gastric cancer development has remained unclear. This study aims to analyze the expression of miR-584 in gastric cancer samples and investigates the associations between this miRNA and H. pylori infection and clinical characteristics. METHODS: The expression level of miR-584 was studied in primary gastric cancers versus healthy control gastric mucosa samples using the RT-qPCR method. The clinical data were analyzed statistically in terms of miR-584 expression. In silico studies were employed to study miR-584 more broadly in order to assess its expression and find new potential target genes. RESULTS: Both experimental and in silico studies showed up-regulation of miR-584 in patients with gastric cancer. This up-regulation seems to be induced by H. pylori infection since the infected samples showed increased levels of miR-584 expression. Deeper analyses revealed that miR-584 undergoes a dramatic down-regulation in late stages, invasive and lymph node-metastatic gastric tumors. Bioinformatics studies demonstrated that miR-584 has a substantial role in cancer pathways and has the potential to target STAT1 transcripts. Consistent with the inverse correlation between TCGA RNA-seq data of miR-584 and STAT1 transcripts, the qPCR analysis showed a significant negative correlation between these two RNAs in a set of clinical samples. CONCLUSION: miR-584 undergoes up-regulation in the stage of primary tumor formation; however, becomes down-regulated upon the progression of gastric cancer. These findings suggest the potential of miR-584 as a diagnostic or prognostic biomarker in gastric cancer.
Subject(s)
Biomarkers, Tumor/metabolism , Gene Expression Regulation, Neoplastic , Helicobacter Infections/genetics , MicroRNAs/metabolism , Stomach Neoplasms/genetics , Adult , Aged , Case-Control Studies , Computational Biology , Down-Regulation , Female , Gastric Mucosa/microbiology , Gastric Mucosa/pathology , Helicobacter Infections/diagnosis , Helicobacter Infections/microbiology , Helicobacter Infections/pathology , Helicobacter pylori/isolation & purification , Host-Pathogen Interactions/genetics , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Grading , Prognosis , RNA-Seq , STAT1 Transcription Factor/genetics , Stomach Neoplasms/diagnosis , Stomach Neoplasms/microbiology , Stomach Neoplasms/mortality , Survival Rate , Up-RegulationABSTRACT
WW domain-binding protein 2 (WBP2) is an emerging oncoprotein. Over the past decade, WBP2 surfaced as a key node connecting key signaling pathways associated with ER/PR, EGFR, PI3K, Hippo, and Wnt in cancer. In addition to the oncogenic functions of WBP2, this review discusses the latest research regarding the multilevel regulation and modes of action of WBP2 and how they can be exploited for molecular medicine. In translational research, evidence supports the role of WBP2 as a biomarker for early detection, prognosis, and companion diagnostics in breast cancer. Finally, we envision new trends in WBP2 research in the space of molecular etiology of cancer, targeted therapeutics, and precision medicine.
Subject(s)
Breast Neoplasms/metabolism , Oncogene Proteins/metabolism , Trans-Activators/metabolism , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Humans , Oncogene Proteins/genetics , Trans-Activators/geneticsABSTRACT
A genetic variant may alter a gene expression level and as a result be associated with pathological characteristics in breast cancer. In this research, the frequency and association of the ErbB4 3'-untranslated region (3'-UTR) variant, rs12471583 (c.*3622A>G) was studied in an Iranian breast cancer patients. In silico assessment was performed to predict the function of the rs12471583 variant located on the 3'-UTR of ErbB4. Furthermore, as a case-control study, this polymorphism was genotyped in 243 breast cancer patients and non-cancerous controls using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The Armitage's trend test and regular association tests were performed to analyze a possible association between the rs12471583 and risk of breast cancer and its relevant pathological traits. The bioinformatics analysis predicted that the rs12471583 SNP is located on the four miRNA binding sites, including miR-511-5p, miR-4659a-5p, miR-4659b-5p, and miR-6830-3p. According to logistic regression tests, the G allele is negatively associated with ER- (OR = 0.20, 95% C.I. = 0.04-0.93, p = 0.026), PR- (OR = 0.31, 95% C.I. = 0.10-0.98, p = 0.039), ER-/PR- (OR = 0.20, 95% C.I. = 0.04-0.93, p = 0.026), and advanced breast cancer (OR = 0.40, 95% C.I. = 0.18-0.85, p = 0.016). It has been found that ErbB4 expression may be linked to unfavorable outcomes in breast cancer. Likewise, our results suggest that the G allele may strengthen miRNA-ErbB4 binding efficiency and as a result reduce expression of ErbB4. This is a possible explanation for the observed association.
ABSTRACT
OBJECTIVE: Multiple sclerosis (MS) is a chronic disorder involving both inflammatory and neurodegenerative responses. Long non-coding RNAs (lncRNAs) have been had an emerging role as the biomarkers of different disorders, including autoimmune diseases. Previous studies have shown that NR_003531.3 (MEG3a), AC000061.1_201, and AC007182.6 play a role in the pathogenesis of human autoimmune diseases. However, the potential significance of these lncRNAs, as the diagnostic biomarkers of MS, has not been studied yet. We aimed to quantitatively evaluate the expression levels of NR_003531.3, AC000061.1_201, and AC007182.6 in peripheral blood samples of MS patients in comparison with healthy controls. MATERIALS AND METHODS: In this case-control study, the blood samples from 20 MS patients and 10 healthy controls were collected. Total RNA was extracted, and the expression levels of three selected lncRNAs were quantitatively measured using the quantitative real time-polymerase chain reaction (qRT-PCR) method. RESULTS: We detected a significant down-regulation in the expression of NR_003531.3 in MS patients, while no marked changes were observed in the expression of AC000061.1_201 and AC007182.6 in patients compared with controls. Based on the receiver operating characteristic (ROC) curve analysis, NR_003531.3 could discriminate MS patients from healthy subjects effectively. Regarding the prognosis of MS patients, NR_003531.3 is significantly and inversely correlated with the expanded disability status scale (EDSS). CONCLUSION: The potential role of NR_003531.3 lncRNA as a diagnostic biomarker to distinguish MS patients is proposed. Prognostically, NR_003531.3 correlates with lower disability rates in MS patients.
ABSTRACT
OBJECTIVE: Gastric cancer is a multifactorial disease. In addition to environmental factors, many genes are involved in this malignancy. One of the genes associated with gastric cancer is CD44 gene and its polymorphisms. CD44 gene plays role in regulating cell survival, growth and mobility. The single nucleotide polymorphism (SNP) rs8193, located in the CD44 gene, has not been studied in gastric cancer patients of the Iranian population. The present study aims to study this polymorphism in 86 gastric cancer patients and 96 healthy individuals. MATERIALS AND METHODS: In this cross-sectional case-control study, rs8193 polymorphism was genotyped by allele specific primer polymerase chain reaction (ASP-PCR) technique. The obtained data were statistically analyzed. To find the potential mechanism of action, rs8193 was bioinformatically investigated. RESULTS: rs8193 C allele played a risk factor role for gastric cancer. Patients carrying this allele were more susceptible to have gastric cancer, with lymph node spread. On the other hand, rs8193 T allele, a protective factor, was associated with a higher chance of accumulation in the lower stages of cancer. C allele might impose its effect via destabilizing CD44 and miR-570 interaction. CONCLUSION: rs8193 is statistically associated with the risk of malignancy, lymph node spread and stage of gastric cancer in Iranian population.
ABSTRACT
Breast cancer is a major cause of cancer-related death in women worldwide. miRNAs are new players of breast tumorigenesis, used as diagnostic and prognostic biomarkers. Among various miRNAs, miR-126 has been proposed to have a tumor suppressive role in HER2 positive cancer. However, to have a better understanding of its role, further validation is required. The aim of this study was evaluating miR-126 expression level in breast cancer tissues and investigating its potential association with HER2, estrogen and progesterone receptors. miR-126 expression level was measured in 108 specimens including 78 malignant and 30 normal samples using RT-qPCR. The outcome was statistically analyzed. In silico studies were performed to find the potential mechanism of action, through which miR-126 imposes its function. Down-regulation of miR-126 was observed in tumor samples, as compared to the matched normal tissues. Down-regulation of miR-126 was also associated significantly with the absence of estrogen receptor in malignant samples. No association between miR-126 expression and HER2 status was observed. Our in silico analyses showed the possible role of Crk, PI3K and Ras proto-oncogenes in breast cancer tumorigenesis. miR-126 is significantly down-regulated in breast cancer tissues. Statistically, it showed no correlation with HER2 positivity. However, the association between lower miR-126 and estrogen receptor negativity was observed.