Mitogen- and stress-activated protein kinase (MSK1/2) regulated gene expression in normal and disease states.

The mitogen- and stress-activated protein kinases (MSK) are epigenetic modifiers that regulate gene expression in normal and disease cell states. MSK1 and 2 are involved in a chain of signal transduction events bringing signals from the external environment of a cell to specific sites in the genome. MSK1/2 phosphorylate histone H3 at multiple sites, resulting in chromatin remodeling at regulatory elements of target genes and the induction of gene expression. Several transcription factors (RELA of NF-κB and CREB) are also phosphorylated by MSK1/2 and contribute to induction of gene expression. In response to signal transduction pathways, MSK1/2 can stimulate genes involved in cell proliferation, inflammation, innate immunity, neuronal function, and neoplastic transformation. Abrogation of the MSK-involved signaling pathway is among the mechanisms by which pathogenic bacteria subdue the host's innate immunity. Depending on the signal transduction pathways in play and the MSK-targeted genes, MSK may promote or hinder metastasis. Thus, depending on the type of cancer and genes involved, MSK overexpression may be a good or poor prognostic factor. In this review, we focus on mechanisms by which MSK1/2 regulate gene expression, and recent studies on their roles in normal and diseased cells.

Bioinformatic Analyses of Broad H3K79me2 Domains in Different Leukemia Cell Line Data Sets.

A subset of expressed genes is associated with a broad H3K4me3 (histone H3 trimethylated at lysine 4) domain that extends throughout the gene body. Genes marked in this way in normal cells are involved in cell-identity and tumor-suppressor activities, whereas in cancer cells, genes driving the cancer phenotype (oncogenes) have this feature. Other histone modifications associated with expressed genes that display a broad domain have been less studied. Here, we identified genes with the broadest H3K79me2 (histone H3 dimethylated at lysine 79) domain in human leukemic cell lines representing different forms of leukemia. Taking a bioinformatic approach, we provide evidence that genes with the broadest H3K79me2 domain have known roles in leukemia (e.g., JMJD1C). In the mixed-lineage leukemia cell line MOLM-13, the HOXA9 gene is in a 100 kb broad H3K79me2 domain with other HOXA protein-coding and oncogenic long non-coding RNA genes. The genes in this domain contribute to leukemia. This broad H3K79me2 domain has an unstable chromatin structure, as was evident by enhanced chromatin accessibility throughout. Together, we provide evidence that identification of genes with the broadest H3K79me2 domain will aid in generating a panel of genes in the diagnosis and therapeutic treatment of leukemia in the future.

Association between Genetic Polymorphisms of miR-1307, miR- 1269, miR-3117 and Breast Cancer Risk in a Sample of South East Iranian Women.

INTRODUCTION: MicroRNAs (miRNAs) play an essential role in the susceptibility and development of cancer cells. OBJECTIVE: Examining the dependency of breast cancer risk with genetic polymorphisms of miR-1307, miR-1269, and miR-3117 in a sample of Iranian women (southeast region). METHODS: The case-control study consisted of 520 individuals (260 diagnosed BC patients, 260 healthy individuals). The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping of miR-1307 rs7911488, miR-1269 rs73239138, and miR-3117 (rs4655646 and rs7512692) polymorphisms. RESULTS AND CONCLUSION: This study provided evidence that miR-1307 rs7911488 polymorphism significantly reduced the risk of BC in heterozygous AG genotype, as well as dominant (AG+GG) genotype and G allele. A significant correlation was found between dominant (AA+AG) genotype, the A allele and protection against BC due to miR-1269 rs73239138 in the sample of study. In contrast, our findings suggested that AG genotype and G allele of miR-3117 rs4655646 polymorphism could increase BC's susceptibility among the southeastern Iranian females. The miR-3117 rs7512692 variant also increased the risk of BC in codominant, dominant and recessive models, as well as the T allele. The possible dependency of miR-1307, miR-1269, and miR-3117 variants with patients' clinicopathological characteristics and BC was also studied. It was concluded that there is a correlation between miR-3117 rs7512692 variant and tumor grade (p=0.031); also, a correlation between miR-1269 rs73239138 variant and progesterone receptor status (p=0.006). The current investigation revealed that miR-1307, miR-1269, and miR-3117 polymorphisms might play a crucial role in the Iranian population's vulnerability to BC.
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Evaluating the Possible Association between PD-1 (Rs11568821, Rs2227981, Rs2227982) and PD-L1 (Rs4143815, Rs2890658) Polymorphisms and Susceptibility to Breast Cancer in a Sample of Southeast Iranian Women.

INTRODUCTION: Programmed cell death-1 (PD-1) and its ligands (PD-L1 and PD-L2) play a critical role as a  regulator of immune-system cells, including T cell, natural killer T (NKT), monocytes, dendritic cells (DC), and B cells. OBJECTIVE: This study aimed to find a possible association between PD-1 (rs11568821, rs2227981, rs2227982), and PD-L1 (rs4143815, rs2890658) variants and Breast Cancer (BC) risk in a sample of southeast Iranian women. METHOD: The case-control study consisted of 520 individuals, including 260 histologically confirmed BC patients and 260 non-cancer age-matching healthy women as the control group. The Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and Tetra-Primer Amplification Refractory Mutation System-Polymerase Chain Reaction (T-ARMS-PCR) methods were used for genotyping of PD-1 (rs11568821, rs2227981, rs2227982), and PD-L1 (rs4143815, rs2890658) polymorphisms. RESULTS AND CONCLUSION: Our findings indicated that the PD-L1 rs4143815 (G/C) variant meaningfully reduced the risk of BC. However, the PD-L1 rs2890658 variant increased the BC risk in the AC genotype as well as the A allele. Furthermore, we could not find a meaningful association between PD-1 rs11568821, PD-1 rs2227981, PD-1 rs2227982, and BC. Our team examined the possible association between variants and clinicopathological characteristics, including age, size of tumour, lymph node, histology, grade of tumour, estrogen and progesterone receptors status as well as human growth factor receptor 2 (HER2). Our findings demonstrated that PD-L1 rs4143815, PD-L1 rs2890658, PD-1 rs2227982 had a significant association with age. Additionally, we found a significant relation between PD-1 rs2227982 variant and tumour size. Statistical analyzes of PD-1 rs2227981 and PD-1 rs11568821 variants showed a meaningful relation between tumour grade and tumour stage (p=0.006), respectively.
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Long non-coding RNA POLR2E gene polymorphisms increased the risk of prostate cancer in a sample of the Iranian population.

The current study aimed to examine the impact of POLR2E rs1046040 and rs3787016 polymorphisms on prostate cancer (PCa) risk in a sample of southeast Iranian population. The present case-control study was performed on 178 patients with PCa and 180 benign prostatic hyperplasia (BPH). Genotyping of the variants was done by mismatch PCR-RFLP. The findings showed that the rs3787016 C > T variant significantly increased the risk of PCa in codominant (OR = 1.84, 95% CI = 1.12-3.03, P = 0.018, CT vs CC), dominant (OR = 1.88, 95% CI = 1.63-3.05, P = 0.011, CT + TT vas CC) and allele (OR = 1.77, 95% CI = 1.52-2.72, P = 0.010, T vs C) inheritance model. Regarding rs1046040 C > T polymorphism, the findings revealed that the CT genotype significantly increased the risk of PCa compared to the CC genotype (OR = 1.60, 95% CI = 1.03-2.49, P = 0.043). Furthermore, rs3787016 CT/rs1046040 CC as well as rs3787016 CT/rs1046040 CT increased the risk of PCa compared to the CC/CC genotype (p = 0.029 and p = 0.014, respectively). Haplotype analysis proposed that rs3787016 T/rs1046040 C significantly increased the risk of PCa compared to C/C (p = 0.037). No significant association was observed between POLR2E variants and clinicopathological characteristics of PCa patients. In conclusion, the findings propose that POLR2E variants may be a risk factor for susceptibility to PCa in a sample of Iranian population.

Detection of a 4-bp Insertion/deletion Polymorphism within the Promoter of EGLN2 Using Mismatch PCR-RFLP and Its Association with Susceptibility to Breast Cancer

It has been shown that a 4-bp insertion/deletion (ins/del) polymorphism of EGLN2 influences the risk of several cancers. However, to date, no study has inspected the impact of the 4-bp ins/del polymorphism on breast cancer (BC) risk. A case-control study, including 134 breast cancer patients and 154 healthy women, was here conducted to examine the possible association between EGLN2 4-bp ins/del polymorphism and BC risk in a southeast Iranian population. A mismatched polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was designed for genotyping of the variant. Our findings did not support any association between the 4-bp ins/del polymorphism and the risk of BC in the codominant, dominant, recessive and allele inheritance models tested. When links between the EGLN2 4-bp ins/del polymorphism and clinicopathological characteristics of the patients were evaluate the variant was only associated with HER2 status. More studies with larger sample sizes and diverse ethnicities are warranted to verify our finding.

Association between genetic polymorphisms of long non-coding RNA PRNCR1 and prostate cancer risk in a sample of the Iranian population.

The aim of the present study was to determine whether there is an association between the long non-coding RNA (lncRNA) prostate cancer-associated non-coding RNA 1 (PRNCR1) polymorphisms and prostate cancer (PCa) risk in a sample of the Iranian population. This case-control study was performed on 178 patients with PCa and 180 subjects with benign prostatic hyperplasia (BPH). Genotyping assay was performed by polymerase chain reaction-restriction fragment length polymorphism. The findings indicated that the GG genotype of the rs13252298 A>G variant significantly increased the risk of PCa (odds ratio=3.49, 95% confidence interval: 1.79-6.81, P=0.0001) compared with AA+AG. As regards the rs1456315 G>A polymorphism, the AG genotype and G allele significantly increased the risk of PCa. As regards the rs7841060 T>G variant, the findings demonstrated that this TG genotype and the G allele significantly increased the risk of PCa. The rs7007694 T>C variant was not found to be associated with the risk of PCa. Haplotype analysis indicated that GTGA and GTGG significantly increased the risk of PCa compared with rs1456315A/rs7007694T/rs7841060T/rs13252298G (ATTG). The PRNCR1 variants were not found to be significantly associated with the clinicopathological characteristics of PCa patients. In conclusion, our findings support an association between PRNCR1 variants and the risk of PCa in a sample of the Iranian population.

Genetic polymorphisms of HOTAIR gene are associated with the risk of breast cancer in a sample of southeast Iranian population.

There is an increasing body of evidence which highlights the critical functions of long non-coding RNAs in the carcinogenicity mechanism of a variety of cancers. It has been reported that HOX transcript antisense intergenic RNA, a member of long non-coding RNA family, increases breast cancer risk. To date, no data regarding the association between HOX transcript antisense intergenic RNA polymorphisms and the risk of breast cancer development has been reported in Iran. Here, we examine the possible association between HOX transcript antisense intergenic RNA gene polymorphisms and breast cancer in a sample of southeast Iranian female population. The HOX transcript antisense intergenic RNA rs920778, rs12826786, rs4759314, and 1899663 gene polymorphisms were genotyped in 220 cases and 231 controls by polymerase chain reaction-restriction fragment length polymorphism. Our findings indicated that rs920778 polymorphism has significant positive association with breast cancer; rs12826786 and rs1899663 polymorphisms demonstrated significant negative association with breast cancer; and the rs4759314 variant was not associated with breast cancer risk. Haplotype analysis revealed that TGAC, CTAT, and TTAT haplotypes significantly decreased the risk of breast cancer compared with rs920778T/rs1899663G/rs4759314A/rs12826786T haplotype. In conclusion, we investigated only four variants of HOX transcript antisense intergenic RNA gene, and the findings suggest that HOX transcript antisense intergenic RNA rs920778, rs12826786, and rs1899663 polymorphisms may be associated with breast cancer risk in a sample of southeast Iranian population. Further replication studies with other polymorphisms of HOX transcript antisense intergenic RNA gene involving a greater sample size and different ethnicities are necessary to verify our findings.

Evaluation of a 3-base pair indel polymorphism within pre-microRNA-3131 in patients with prostate cancer using mismatch polymerase chain reaction-restriction fragment length polymorphism.

The present study aimed to examine the impact of a 3-bp indel (rs57408770) polymorphism within the pre-microRNA (miR)-3131 polymorphism on prostate cancer (PCa) risk in a sample of an Iranian population. In total, 340 subjects, including 177 patients with PCa and 170 patients with benign prostatic hyperplasia, were enrolled in the present case-control study. A mismatch polymerase chain reaction-restriction fragment length polymorphism method was designed for genotyping the 3-bp indel (rs57408770) polymorphism. The present findings demonstrated that the indel variant significantly increased the risk of PCa in codominant [odds ratio (OR)=2.23, 95% confidence interval (CI)=1.13-4.37; P=0.021, insertion (ins)/ins vs. deletion (del)/del] and recessive (OR=2.33, 95% CI=1.25-4.36; P=0.009, ins/ins vs. del/del + del/ins). In conclusion, to the best of our knowledge, the present findings for the first time proposed that a 3-bp indel variant of miR-3131 may be a risk factor for susceptibility to PCa in a sample of an Iranian population. Further studies with different ethnicities and larger sample sizes are required to validate the present findings.