SBF2-AS1 and TreRNA: novel lncRNA players in triple-negative breast cancer pathogenesis.

BACKGROUND: Compared to other breast cancer subtypes, triple-negative breast cancer (TNBC) has always been challenging for clinicians due to its aggressive behavior and lack of a specific treatment. There is a confirmed association between invasive features of tumors and increased epithelial-mesenchymal transition (EMT) process, which is consistent with a higher rate of EMT in TNBC. METHODS AND RESULTS: We investigated the expression of EMT-related genes, SNAI1 and MMP7, and EMT-related lncRNAs, treRNA and SBF2-AS1, in 50 TNBC tumors and 50 non-TNBC tumors to reveal more regulators and effectors involved in TNBC malignancy. In the present study, we showed the overexpression of all the studied genes and lncRNAs in TNBC tumors compared to non-TNBC samples. Moreover, a significant association was observed between MMP7 and treRNA expression levels and larger tumor size. A positive correlation between SNAI1 and lncRNA treRNA expression levels was also detected. CONCLUSIONS: Due to the differential expression and the potential diagnostic power of the studied genes, SBF2-AS1 and treRNA can be proposed as new probable biomarkers and therapeutic targets in TNBC.

The role of FOXC1/FOXCUT/DANCR axis in triple negative breast cancer: a bioinformatics and experimental approach.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer and does not benefit from the existing targeted therapies. In the present study, we used bioinformatics and experimental approaches to assess the genes that are somehow involved in the epithelial-mesenchymal transition (EMT) pathway which may explain the invasive features of TNBC. METHOD AND RESULTS: We analyzed five GEO datasets consisting of 657 breast tumors by GEO2R online software to achieve common differentially expressed genes (DEGs) between TNBC and non-TNBC tumors. The expression of the selected coding and non-coding genes was validated in 100 breast tumors, including fifty TNBC and fifty non-TNBC samples, using quantitative Real-Time PCR (qRT-PCR). The bioinformatics approach resulted in a final DEG list consisting of ten upregulated and seventeen downregulated genes (logFC ≥|1| and P < 0.05). Co-expression network construction indicated the FOXC1 transcription factor as a central hub node. Considering the notable role of FOXC1 in EMT, the expression levels of FOXC1-related lncRNAs, lnc-FOXCUT and lnc-DANCR, were also evaluated in the studied tumors. The results of qRT-PCR confirmed notable upregulation of FOXC1, lnc-FOXCUT, and lnc-DANCR in TNBC tissues compared to non-TNBC samples (P < 0.0001, P = 0.0005, and P = 0.0008, respectively). Moreover, ROC curve analysis revealed the potential biomarker role of FOXC1 in TNBC samples. CONCLUSION: Present study suggested that the deregulation of FOXC1/lnc-FOXCUT/lnc-DANCR axis may contribute to the aggressive features of triple-negative breast tumors. Therefore, this axis may be considered as a new probable therapeutic target in the treatment of TNBC.

Circular RNA hsa_circ_0044234 as distinct molecular signature of triple negative breast cancer: a potential regulator of GATA3.

BACKGROUND: Circular RNAs (circRNAs) have been implicated in the initiation and development of breast cancer as functional non-coding RNAs (ncRNA). The roles of circRNAs as the competing endogenous RNAs (ceRNAs) to sponge microRNAs (miRNAs) have also been indicated. However, the functions of circRNAs in breast cancer have not been totally elucidated. This study aimed to explore the clinical implications and possible roles of circ_0044234 in carcinogenesis of the most problematic BC subtype, triple negative breast cancer (TNBC), which are in desperate need of biomarkers and targeted therapies. METHODS: The importance of circ_0044234 as one of the most dysregulated circRNAs in TNBC was discovered through microarray expression profile analysis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to confirm the downregulation of circ_0044234 in triple negative tumors and cell lines versus non-triple negative ones. The bioinformatics prediction revealed that circ_0044234 could act as an upstream sponge in the miR-135b/GATA3 axis, two of the most dysregulated transcripts in TNBC. RESULTS: Our experimental investigation of circ_0044234 expressions in various BC subtypes as well as cell lines reveals that TNBC expresses circ_0044234 at a substantially lower level than non-TNBC. The ROC curve analysis indicates that it could be applied as a discriminative biomarker to identify TNBC from other BC subtypes. Moreover, circ_0044234 expression could be an independent prognostic biomarker in BC. Interestingly, a substantial inverse expression correlation was detected between circ_0044234 and miR-135b-5p as well as between miR-135b-5p and GATA3 in breast tumors. CONCLUSIONS: The possible clinical usefulness of circ_0044234 as a promising distinct biomarker and upcoming therapeutic target for TNBC have been indicated in this research. Our comprehensive approach revealed the potential circ_0044234/miR135b-5p/GATA3 ceRNA axis in TNBC.

Dysregulation of vitamin D synthesis pathway genes in colorectal cancer: A case-control study.

BACKGROUND: The cytochromes P450 are a superfamily of enzymes that control the synthesis of the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3. These enzymes contribute to the formation of 1,25-dihydroxyvitamin D3, which starts with a 25-hydroxylation by CYP2R1 and CYP27A1 and a subsequent 1α-hydroxylation via CYP27B1. METHODS: By using quantitative real-time polymerase chain reaction (qRT-PCR), we analyzed the expression ratio of CYP2R1, CYP27A1 and CYP27B1 genes within the vitamin D metabolic pathway in a total of 75 colorectal cancer (CRC) tissues compared to the adjacent tissues. Furthermore, we evaluated the association of CYP27B1 rs4646536 and CYP2R1 rs12794714 and rs10766196 polymorphisms with CRC risk in a total of 490 subjects, including 245 CRC patients and 245 non-cancer controls. The genotyping was performed using tetra-primer amplification refractory mutation system polymerase chain reaction (TP-ARMS-PCR) method. RESULTS: The results indicated 2.3 and 2.7 upregulation of CYP2R1 and CYP27B1 genes in colorectal cancer tissues compared to the adjacent tissues, respectively. Rs12794714 AG genotype increased the risk of CRC (P = .03). Furthermore, a significant association was observed under the dominant inheritance model (P = .039). CONCLUSION: CYP2R1 and CYP27B1 genes were over-expressed in CRC samples compared to the adjacent control tissues. Furthermore, CYP2R1 rs12794714 variant was associated with the risk of CRC in the studied samples. CYP2R1 rs10766196 and CYP27B1 rs4646536 are not responsible for CYP2R1 and CYP27B1 genes expression alteration, respectively, but CYP2R1 rs12794714 polymorphism may be the reason of CYP2R1 upregulation and increased the risk of CRC.

Zinc finger proteins: guardians of genome stability.

Zinc finger proteins (ZNF), a unique yet diverse group of proteins, play pivotal roles in fundamental cellular mechanisms including transcription regulation, chromatin remodeling, protein/RNA homeostasis, and DNA repair. Consequently, the mis regulation of ZNF proteins can result in a variety of human diseases, ranging from neurodevelopmental disorders to several cancers. Considering the promising results of DNA damage repair (DDR) inhibition in the clinic, as a therapeutic strategy for patients with homologous recombination (HR) deficiency, identifying other potential targetable DDR proteins as emerged vulnerabilities in resistant tumor cells is essential, especially when considering the burden of acquired drug resistance. Importantly, there are a growing number of studies identifying new ZNFs and revealing their significance in several DDR pathways, highlighting their great potential as new targets for DDR-inhibition therapy. Although, there are still many uncharacterized ZNF-containing proteins with unknown biological function. In this review, we highlight the major classes and observed biological functions of ZNF proteins in mammalian cells. We briefly introduce well-known and newly discovered ZNFs and describe their molecular roles and contributions to human health and disease, especially cancer. Finally, we discuss the significance of ZNFs in DNA repair mechanisms, their potential in cancer therapy and advances in exploiting ZNF proteins as future therapeutic targets for human disease.

Investigation of piwi-interacting RNA pathway genes role in idiopathic non-obstructive azoospermia.

Genes involved in piwi-interacting RNAs (piRNAs) pathway have an essential role in spermatogenesis. HIWI and TDRD proteins are critical for piRNA biogenesis and function. Therefore, Mutations and polymorphisms in HIWI and TDRD genes may play role in male infertility. The aim of the present study was to investigate the role of HIWI2 rs508485 (T>C) and HIWI3 rs11703684 (C>T) polymorphisms and mutational analysis of TDRD5 gene in idiopathic non-obstructive azoospermia in a case-control study including 226 non-obstructive azoospermia patients and 200 fertile males. Genotyping for both polymorphisms was performed using Tetra-Primer ARMS PCR. Mutation analysis of TDRD5 gene was done using multi-temperature single strand conformation polymorphism technique (MSSCP). The frequency of rs508485TC genotype was significantly different in the studied groups (P = 0.0032; OR = 2.12; 95% CI, 1.29-3.48). In addition, the genotype frequencies showed a significant difference under dominant model (P = 0.005; OR = 2.79; 95% CI, 1.22-3.13). No mutation was detected in the Tudor domain of the TDRD5 in the studied patients. In conclusion, we provide evidence for association between genetic variation in the HIWI2 gene and idiopathic non-obstructive azoospermia in Iranian patients. Therefore, piRNA pathway genes variants can be considered as risk factors for male infertility.

HIWI2 rs508485 Polymorphism Is Associated with Non-obstructive Azoospermia in Iranian Patients.

BACKGROUND: The PIWI-interacting RNA (piRNA) pathway has an essential role in transposon silencing, meiosis progression, spermatogenesis, and germline maintenance. HIWI genes are critical for piRNA biogenesis and function. Therefore, polymorphisms in HIWI genes contribute to spermatogenesis defects and can be considered as risk factors for male infertility. The aim of the present study was to investigate the association between the HIWI2 gene rs508485 polymorphism and non-obstructive azoospermia. METHODS: A total of 121 Iranian men with idiopathic azoospermia and 100 fertile controls were genotyped for HIWI2 rs508485 (T>C) polymorphism using Tetra-ARMS PCR. The presence of eight sequence-tagged site (STS) markers from the Y chromosome AZF region was also investigated by Multiplex PCR (M-PCR). RESULTS: Thirteen (10.74%) patients showed Y chromosome microdeletions and therefore were excluded from the study. rs508485 in the 3'UTR of HIWI2 was associated with increased risk of azoospermia in our studied population with a P-value of 0.035 and odds ratio of 2.00 (CI 95%: 1.04-3.86). CONCLUSIONS: We provide evidence for an association between genetic variation in the HIWI2 gene involved in the piRNA pathway and idiopathic non-obstructive azoospermia in Iranian patients. Therefore, piRNA pathway gene variants can be considered as risk factors for male infertility.