Expression patterns of T cells-specific long noncoding RNAs in systemic lupus erythematosus patients carrying HLA risk/nonrisk alleles.

BACKGROUND: Long noncoding RNAs (LncRNAs) play key roles in the regulation of gene expression and subsequently in the pathogenesis of several autoimmune diseases. This study aimed to explore the peripheral expression levels of T-cells-specific LncRNAs and transcription factors in systemic lupus erythematosus (SLE) patients carrying either human leukocyte antigens (HLA) risk or non-risk alleles. METHODS: Genotypes of HLA-DRB1 and HLA-DQB1 loci for 106 SLE patients were determined by PCR-SSP. In the next step, patients were stratified based on the presence of HLA-DRB1*03 and/or DRB1*16 allele groups (HLA risk alleles positive or HLA-RPos) or carrying other DRB1 allele groups (HLA-RNeg). Then, transcript levels of LncRNAs (IFNG-AS1, RMRP, Th2LCR, and DQ786243) and mRNAs for transcription factors (Foxp3, Gata3, and Tbx21) were measured using qRT-PCR and compared between two subgroups of patients. RESULTS: Totally, 47 cases were classified as HLA-RPos and 59 cases as HLA-RNeg patients. The HLA-RPos patients showed decreased transcript levels of DQ786243 (p = .001) and elevated expression of IFNG-AS1 (p = .06) and T-bet mRNA (p = .03) compared to the HLA-RNeg group. We observed significantly lower expression of Th2LCR (p < .0001) and DQ786243 (p = .001) and higher expression of Tbx21 (p = .009) and Foxp3 (p = .02) in DR3-positive versus DR3-negative patients. Likewise, decreased transcript levels of DQ786243 (p = .02) and RMRP (p = .003) were observed in DR16-positive versus DR16-negative patients. ROC curve analysis revealed the potential of DQ786243 and RMRP as biomarkers in SLE disease based on the carriage of HLA risk alleles. CONCLUSIONS: Our results indicate that the contribution of multiple T cell subsets in SLE disease progression as judged by expression analysis of LncRNAs and transcription factors can be inspired by the inheritance of HLA risk/nonrisk alleles is SLE patients.

In vitro co-delivery of 5-fluorouracil and all-trans retinoic acid by PEGylated liposomes for colorectal cancer treatment.

BACKGROUND: Single-target inhibitors have not been successful in cancer treatment due to the development of drug resistance. Nevertheless, therapeutic agents capable of simultaneously inhibiting multiple targets have revealed encouraging results in inducing apoptosis and overcoming drug resistance in cancerous cells. Here, we designed a composite liposomal nano-carrier co-loading 5-Fluorouracil (5-FU) with all-trans retinoic acid (ATRA) to assess anticancer efficacy of the combined drugs in colorectal cancer (CRC). METHODS: A PEGylated liposomal nano-carrier with phospholipid/cholesterol/DSPE-PEG (2000) was synthesized by the thin film hydration technique for co-delivery of ATRA and 5-FU. After characterizing, the role of 5-FU and ATRA co-loaded liposomal nano-carrier in proliferation, epithelial-mesenchymal transition (EMT), apoptosis, and cancer stem cells (CSCs) were investigated by using colony forming and MTT assay, RT-qPCR and Annexin V/PI kit. RESULTS: The average size of liposomes (LPs) was < 150 nm with uniform size distribution. Drug release analyses indicated that both ATRA and 5-FU could simultaneously release from LPs in a sustained release manner. The synergistic inhibitory effects of ATRA and 5-FU loaded in LPs were verified with a combination index of 0.43. Dual drug LPs showed the highest cytotoxicity, enhanced inhibition of cell proliferation, increased apoptotic potential, decreased CSCs, and attenuated EMT-associated biomarkers. Also, dual drug LPs decreased ß-catenin gene expression more than other liposomal formulations. CONCLUSION: These findings suggest that using LPs to achieve a synergistic effect of ATRA and 5-FU is an effectual approach to increase the therapeutic effect of 5-FU toward CRC cells.

Investigating the role of peptides in effective therapies against cancer.

Early diagnosis and effective treatment of cancer are challenging. To diagnose and treat cancer effectively and to overcome these challenges, fundamental innovations in traditional diagnosis and therapy are necessary. Peptides can be very helpful in this regard due to their potential and diversity. To enhance the therapeutic potential of peptides, their limitations must be properly identified and their structures engineered and modified for higher efficiency. Promoting the bioavailability and stability of peptides is one of the main concerns. Peptides can also be effective in different areas of targeting, alone or with the help of other therapeutic agents. There has been a lot of research in this area, and the potential for variability of peptides will continue to improve this process. Another promising area in which peptides can help treat cancer is peptide vaccines, which are undergoing promising research, and high throughput technologies can lead to fundamental changes in this area. Peptides have been effective in almost all areas of cancer treatment, and some have even gone through clinical phases. However, many barriers need to be overcome to reach the desired point. The purpose of this review is to evaluate the mechanisms associated with peptides in the diagnosis and treatment of cancer. Therefore, related studies in this area will be discussed.

Human exposure to low dose ionizing radiation affects miR-21 and miR-625 expression levels.

BACKGROUND: Recently exposure to ionizing radiation driven by artificial radiation sources such as Medical X-rays and Nuclear medicine has increased hastily. Ionizing radiation-induced the DNA damage and activate the DNA damage response signaling pathways. The aim of this study was to evaluate the role of miR-21 and miR-625 in response to low-dose ionizing radiation. MATERIALS AND METHODS: In this study, the blood sample of 38 volunteer patients who underwent Cardiac scans before and after 99mTc-MIBI injection were used. The WBC of patients was used for RNA extraction and after cDNA synthesis by the poly-A method the expression level of miR-21 and miR-625 was evaluated by real-time PCR method. RESULTS: The results of this study indicated that miR-21 and miR- 625 were significantly upregulated under exposure to low-dose ionizing radiation. The expression level of these miRNAs was not significantly correlated with the age and BMI of patients. More ever the bioinformatics analysis indicated that SP1 was a common target of both miRNAs and had the highest degree between hub genes. CONCLUSION: In summary miR-21 and miR-625 can contribute to the response to acute low dose ionizing radiation by targeting the SP1. However further studies should be carried out on the molecular mechanism of effects of miR-21 and miR-625 in response to low dose ionizing radiation by targeting the SP1.

Assessment of Association between miR-146a Polymorphisms and Expression of miR-146a, TRAF-6, and IRAK-1 Genes in Patients with Brucellosis.

BACKGROUND: Brucellosis is a major zoonosis all over the world. MicroRNAs are significant gene expression regulators and could be involved during the infections and also genetic alterations in the miRNAs sequence can affect primary miRNAs and precursor miRNAs processing and thus alter miRNAs expression. Current research studied the impact of the miR-146a polymorphism on miR-146a, TRAF-6, and IRAK-1 genes expression in patients with brucellosis illness. METHODS AND RESULTS: In this research, 25 patients with brucellosis and 25 healthy participants with determined genotypes for miR-SNP rs2910164 and miR-SNP rs57095329 were recruited. IRAK-1, TRAF-6, and miR-146a expressions in peripheral blood mononuclear cells (PBMCs) were specified by quantitative real- time PCR (qRT-PCR). Moreover, interleukin-1ß (IL-1ß) and tumor necrosis factor- alpha (TNF-α) serum levels were assessed by a sandwich enzyme-linked immunosorbent assay (ELISA) technique. There was no significant difference in the expression level of miR-146a, IRAK-1, and TRAF-6, among the patients with brucellosis and control group. TRAF-6 PBMCs expression levels in the distinctive genotypes of rs2910164 were significantly observed in patients (P = 0.048). No significant distinctions were found in miR-146a, IRAK-1, and TRAF-6 expression levels and among the rs57095329 different genotypes in brucellosis patients and controls. Meanwhile, no significant relationship was found between the rs2910164 and rs57095329 genotypes and the serum level of cytokines mentioned between the two groups. We did not find any association between expression of TRAF-6, miR-146a, and IRAK-1 in PBMCs, and cytokines serum levels with two single nucleotide polymorphisms (SNPs) in miR-146a. CONCLUSIONS: To the best of writers' knowledge, this research is the first one evaluating the probable link between the miR-146a rs2910164 and rs57095329 variant with miRNAs, relevant cytokine levels, and target genes in brucellosis.

Deciphering the role of miR-71 and let-7 in the fertility of cystic echinococcosis cysts: a preliminary assessment.

Cystic echinococcosis (CE) is a neglected helminthic zoonosis in many parts of the world. Some CE cysts in the intermediate host are non-fertile. Considering the function of microRNAs in many biological processes such as embryonic development, cell proliferation, and apoptosis, this study investigated the function and comparison of miR-71 and let-7 in fertile and non-fertile CE cysts. Here, we determined the expression level of the miRNAs for 33 animal cysts and 16 human cysts (Echinococcus granulosus sensu stricto (G1). The quantitative real-time PCR method was conducted for the expression evaluation of miR-71 and let-7. The expression of both miRNAs in all samples was determined using the following formula: [ΔCT = CT (target) - CT (internal control)]. A comparison of Δct of miR-71 and let-7 in fertile and non-fertile cysts did not show a significant difference (P = 0.911 and 0.354). In cattle, sheep, and humans, Δct of miR-71, and let-7 were higher, respectively. Therefore, the mean expression of miR-71 and let-7 indicates an increase in humans compared to other intermediate hosts. Also, statistical results show a significant difference in the expression of these miRNAs in sheep, cattle, and human cysts (P = 0.025 and 0.01). The lower expression of these miRNAs in cattle cysts and their common infertility might be associated with the hypothesis and function of miRNAs in the fertility of CE cysts. So we should not ignore the function and role of miRNAs in this subject due to the importance of infertility in E. granulosus epidemiology.

Near-infrared 940-nm diode laser photobiomodulation of inflamed periodontal ligament stem cells.

Photobiomodulation (PBM) is an acceptable method of stimulating stem cells through its non-invasive absorption by the cell photoreceptors and the induction of cellular response. The current research was aimed at evaluating the effect of near-infrared PBM on proliferation and osteogenic differentiation in inflamed periodontal ligament stem cells (I-PDLSCs). I-PDLSCs were isolated and characterized. Third passage cells were irradiated with 940-nm laser at an output power of 100 mW in a continuous wave. A fluence of 4 J/cm2 in three sessions at 48-h intervals was applied and compared with non-irradiated controls. Cell viability and proliferation were evaluated by MTT assay. Alkaline phosphatase activity, quantitative Alizarin red staining test, and q-RT-PCR were used to evaluate the osteogenic properties of the I-PDLSCs in four groups of (a) osteogenic differentiation medium + laser (ODM + L), (b) osteogenic differentiation medium without laser (ODM), (c) non-osteogenic differentiation medium + laser (L), and (d) non-osteogenic differentiation medium (control). There was a non-significant increase in the viability of cells at 48- and 72-h post last laser irradiation. Alizarin red staining revealed no significant stimulatory effect of PBM at 14 and 21 days. However, alkaline phosphatase activity was significantly higher in the L + ODM group. Expression of osteogenic-related genes had a statistically significant increase at 21-day post irradiation. The irradiation used in the present study showed no significant increase in the proliferation of I-PDLSCs by PBM. However, expression levels of osteogenic-related genes and alkaline phosphatase activity were significantly increased in irradiated groups.

NIR irradiation of human buccal fat pad adipose stem cells and its effect on TRP ion channels.

The effect of near infrared (NIR) laser irradiation on proliferation and osteogenic differentiation of buccal fat pad-derived stem cells and the role of transient receptor potential (TRP) channels was investigated in the current research. After stem cell isolation, a 940 nm laser with 0.1 W, 3 J/cm2 was used in pulsed and continuous mode for irradiation in 3 sessions once every 48 h. The cells were cultured in the following groups: non-osteogenic differentiation medium/primary medium (PM) and osteogenic medium (OM) groups with laser-irradiated (L +), without irradiation (L -), laser treated + Capsazepine inhibitor (L + Cap), and laser treated + Skf96365 inhibitor (L + Skf). Alizarin Red staining and RT-PCR were used to assess osteogenic differentiation and evaluate RUNX2, Osterix, and ALP gene expression levels. The pulsed setting showed the best viability results (P < 0.05) and was used for osteogenic differentiation evaluations. The results of Alizarin red staining were not statistically different between the four groups. Osterix and ALP expression increased in the (L +) group. This upregulation abrogated in the presence of Capsazepine, TRPV1 inhibitor (L + Cap); however, no significant effect was observed with Skf96365 (L + Skf).

The potential role of nucleophosmin (NPM1) in the development of cancer.

Nucleophosmin (NPM1) is a well-known nucleocytoplasmic shuttling protein that performs several cellular functions such as ribosome biogenesis, chromatin remodeling, genomic stability, cell cycle progression, and apoptosis. NPM1 has been identified to be necessary for normal cellular functions, and its altered regulation by overexpression, mutation, translocation, loss of function, or sporadic deletion can lead to cancer and tumorigenesis. In this review, we focus on the gene and protein structure of NPM1 and its physiological roles. Finally, we discuss the association of NPM1 with various types of cancer including solid tumors and leukemia.

Association between risk of brucellosis and genetic variations in MicroRNA-146a.

BACKGROUND: Single nucleotide polymorphisms (SNPs) are the most common types of DNA changes in the human genome that leading to phenotypic differences in humans. MicroRNAs (miRNAs) are usually affected by various bacterial infections, and they are involved in controlling the immune responses. MicroRNA-146a (miR-146a) plays an essential role in the development of infectious and inflammatory diseases. The aim of the present study was to investigate the association between risk of brucellosis and genetic variations in miR-146a. METHODS: This case-control study was conducted on 108 Brucellosis patients and 108 healthy controls. We genotyped two SNPs (rs2910164 and rs57095329) of the miR-146a using tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) methods. RESULTS: The rs2910164 SNP was significantly associated with brucellosis in co-dominant [OR = 4.27, 95% CI = (2.35-7.79, P = 0.001] and dominant [OR = 3.52, 95% CI = (1.97-6.30, P = 0.001] models. Co-dominant (P = 0.047) and recessive (P = 0.018) models were significant at position rs57095329 between the two groups of patient and healthy. The A C haplotype (rs2910164 and rs57095329) was associated with brucellosis in the assessed population [OR (95% CI) = 1.98 (1.22-3.20), P = 0.0059]. CONCLUSIONS: Consequently, our study demonstrated significant differences in genotype and haplotype frequencies of miR-146a variants between brucellosis patients and controls. Further studies on the larger sample sizes are required to verify the observed associations.

Assessment of lncRNA DANCR, miR-145-5p and NRAS axis as biomarkers for the diagnosis of colorectal cancer.

Recent evidence reveals that miRNA sponges neutralize miRNAs activity by binding to miRNAs and sequester them from their relevant targets to regulate expression. The detailed mechanisms of sponge RNAs in colorectal cancer remain to be exactly determined. In this study DANCR, miR-145-5p, NRAS axis was evaluated and the diagnostic value of these targets was assessed in colorectal cancer patients. A case-control study was carried out on 40 samples of tumor tissues and 40 adjacent tissues. Total RNA was extracted, and then, the expression level of DANCR, miR-145-5p and NRAS was evaluated using qRT-PCR. In addition, the sensitivity and specificity of these markers were evaluated by receiver operating characteristic (ROC) curve analysis. Our results revealed that the expression level of DANCR was significantly upregulated in colorectal cancer tissues (p < 0.001). It was demonstrated that DANCR could regulate NRAS expression by sponging miR-145-5 in colorectal cancer patients. Furthermore, the mean expression of miR-145-5p (p < 0.001) and NRAS (p < 0.001) was significantly different between tumor and normal tissue. A significant correlation was observed between DANCR and miR-145-5p (p = 0.001), and also between miR-145-5p and NRAS (p < 0.001). Sensitivity and specificity value for DANCR, miR-145-5p and NRAS were (0.875 and 0.725), (0.875 and 0.745), and (0.877 and 0.694), respectively. According to the values of sensitivities and specificity of DANCR, miR-145-5p and NRAS, confirmed with ROC curve analysis, these biomarkers may be useful in the screening and differentiating between tumor and control sample in colorectal neoplasm.

Investigating the effect of radiosensitizer for Ursolic Acid and Kamolonol Acetate | on HCT-116 cell line.

PURPOSE: The aim of this study was evaluating the cytotoxic and radiosensitizing effects of Ursolic Acid (UA) and Kamolonol Acetate (KA) on HCT116 cell line and finally investigating the functional role of NF-κB and CCND1 genes in the radiosensitizing activity of UA and KA. MATERIALS AND METHOD: The cytotoxic effects of UA and KA by MTT assay was evaluated on HCT-116. Clonogenic assay was performed to investigate of radiosensitizing effects of UA and KA on HCT116. To assessment the expression levels of NF-κB and CCND1 genes, real-time PCR method was used. RESULTS: The results of MTT assay revealed that UA and KA have cytotoxic effects on HCT116 cell line. According to clonogenic assay, survival fraction of treated cells with UA and KA has been decreased compared to the survival fraction of untreated cells. UA and KA lead to the decrease in the expression level of NF-κB. Synergistic effect of radiosensitizing agents with radiation was only approved for UA and 2 Gy of radiation. CONCLUSION: Based on our study, UA and KA have cytotoxic effects on HCT116 cell line. Furthermore, UA may lead to radiosensitization of human colorectal tumor cells by NF-κB1 and CCND1signaling pathways.

Cross-Resistance of Acquired Radioresistant Colorectal Cancer Cell Line to gefitinib and regorafenib.

BACKGROUND: Usually, chemoradiotherapy can be used for the treatment of locally advanced colorectal cancer (CRC) before surgery. On the other hand, some studies have shown that fractional radiation of tumor cells leads to chemoresistance. The aim of this study was to evaluate the chemoresistance of radioresistant sub-line (RR sub-line). METHODS: This study was done in Hamadan University of Medical Sciences in 2017-2018. MTT assay and sub-G1 fraction analysis by flow cytometry were used to evaluate cross-resistance of RR sub-line to gefitinib and regorafenib. Real-time PCR was used to investigate the role of four miRNAs and their target genes in the cross-resistance of RR sub-line. The t test and repeated measures test were used for the assessment of statistical significance between groups. RESULTS: The IC50 of gefitinib and regorafenib for RR sub-line were significantly higher than those of the parental cell line. On the other hand, the resistance index of RR sub-line for gefitinib and regorafenib were 1.92 and 1.44, respectively. The sub-G1 fraction of RR sub-line following treatment with gefitinib and regorafenib was significantly lower than that of the parental cell line (P=0.012 and P=0.038, respectively). The expression of miR-9, Let-7e, and Let-7b in RRsub-line was significantly lower than that of the parental cell line. However, NRAS, IGF1R, NFKB1, and CCND1 found to be upregulated in RR sub-line in comparison with the parental cell line. CONCLUSION: We can conclude that the acquired RR sub-line was cross-resistance to gefitinib and regorafenib. Furthermore, miR-9/NFKB1, let-7b/CCND1, let-7e/NRAS, and IGF1R played essential roles in the chemoradioresistance of CRC.

Let-7e enhances the radiosensitivity of colorectal cancer cells by directly targeting insulin-like growth factor 1 receptor.

Abnormal expression of various microRNAs (miRNAs), as regulators of biological signaling pathways, has a strong association with cancer resistance to chemotherapy and radiotherapy. The let-7 family of miRNAs as tumor suppressors have shown to be downregulated in different types of human malignancies including colorectal cancer (CRC). However, the biological function of let-7 members in the processes of resistance to radiation in CRC has not yet been completely elucidated. Insulin-like growth factor 1 receptor (IGF-1R) signaling pathway is amplified in CRC and leads to its progression, development, and also radiation resistance. So, it seems like an attractive target for anticancer therapy. In this study, by using bioinformatics analysis, it has been revealed that IGF-1R is a direct target of the let-7e member. Consistent with this, we identified that increased levels of let-7e in CRC cells reduced IGF-1R protein level and subsequently its downstream signaling pathways, which resulted in the G1 cell cycle arrest and a significant reduction in the proliferation, survival and also resistance to radiation of CRC cells. Altogether, these results suggested that let-7e by targeting the IGF-1R signaling pathway might serve as therapeutics in anticancer therapy.

Sublethal concentration of H2O2 enhances the protective effect of mesenchymal stem cells in rat model of spinal cord injury.

OBJECTIVE: To investigate the effect of H2O2 on the migration and antioxidant defense of mesenchymal stem cells (MSCs) and the neurotrophic effects of H2O2-treated MSCs on spinal cord injury (SCI). RESULTS: Sublethal concentrations of H2O2 decreased cell migration and expression of CXCR4 and CCR2 as well as Nrf2 expression in MSCs. In the second phase, transplantation of treated and untreated MSCs to SCI caused minor changes in locomotor dysfunction. There was a significantly difference between cell-treated and spinal cord injury groups in expression of BDNF (brain-derived neurotrophic factor). Transplantation of H2O2-treated cells caused an increase in BDNF expression compared to non-treated cells. CONCLUSION: Transplantation of H2O2-treated stem cells may have protective effects against SCI through by increasing neurotrophic factors.

Amelioration of diabetes-induced testicular and sperm damage in rats by cerium oxide nanoparticle treatment.

Cerium oxide nanoparticles (CNPs) as an antioxidant have been used frequently to attenuate hyperglycaemia oxidative damage in different organs. We investigated the impact CNPs on the qualitative and quantitative sperm parameters, spermatogenesis and NFE2-related factor 2 (Nrf2) expression as a major contributor of antioxidant defence in the male diabetic rats. Twenty-four male rats were divided into four groups. Controls received only mouse food and water. Second group were treated with CNPs (30 mg kg-1  day-1 ) for 2 weeks. Rats in third group received streptozotocin (STZ) (60 mg/kg). In fourth group, animals became diabetic and received CNPs (30 mg kg-1  day-1 ) for 2 weeks. The results showed a significant abnormality in the sperm parameters and histopathological patterns of testes in the diabetic group compared to the control group and CNPs treatment significantly improved all testicular parameters. Following CNPs administration, sperm DNA fragmentation significantly reduced in the STZ-treated rats. Moreover, after CNPs intake in the STZ-treated rats, Nfr2 expression levels increased significantly. Overall, CNPs administration on the diabetic rates can attenuate detrimental effects of diabetes on the sperm potential fertility, sperm parameters, DNA integrity and Nrf2 expression levels. This study gives a future prospect to determine the role of CNPs in the context of diabetes.

Hypoxia: A Double-Edged Sword in Cancer Therapy.

Hypoxia is a common feature of malignant tumors. There is an interactive connection between hypoxia and chemoresistance, radioresistance, invasiveness, and angiogenesis. Therefore, tumor hypoxia has been considered as a validated target for treating cancer. This review focuses on the role of hypoxia on chemoresistance and radioresistance. In addition, we address several approaches targeting tumor hypoxia, known as hypoxia-targeted therapy.

Investigation of the effects of different substrates on the promotion of the soil microbial consortium, encompassing bacteria and fungi, in the bioremediation of decabromodiphenyl ether (BDE-209).

Decabromodiphenyl ether (BDE-209) is recognized as an emerging and hazardous pollutant in numerous ecosystems. Despite this, only a few studies have concurrently investigated the biodegradation of BDE-209 by a microbial consortium comprising both bacteria and fungi. Consequently, the interactions between bacterial and fungal populations and their mutual effects on BDE-209 degradation remain unclear. Our main objective was to concurrently assess the changes and activity of bacterial and fungal communities during the biodegradation of BDE-209 in a real soil matrix. In the present study, various organic substrates were employed to promote soil biomass for the biodegradation of BDE-209. Soil respiration and molecular analysis were utilized to monitor biological activity and biomass community structure, respectively. The findings revealed that the use of wheat straw in the soil matrix resulted in the highest soil respiration and microbial activity among the treatments. This approach obviously provided suitable habitats for the soil microflora, which led to a significant increase in the biodegradability of BDE-209 (49%). Biomass survival efforts and the metabolic pathway of lignin degradation through co-metabolism contributed to the biodegradation of BDE-209. Microbial community analysis identified Proteobacteria (Alphaproteobacteria-Betaproteobacteria), Firmicutes, Bacteroides (bacterial phyla), as well as Ascomycota and Basidiomycota (fungal phyla) as the key microorganisms in the biological community involved in the biodegradation of BDE-209. This study demonstrated that applying wheat straw can improve both the biological activity and the biodegradation of BDE-209 in the soil of polluted sites.

Introducing novel key genes and transcription factors associated with rectal cancer response to chemoradiation through co-expression network analysis.

Preoperative radiochemotherapy is a promising therapeutic method for locally advanced rectal cancer patients. However, the response of colorectal cancer (CRC) patients to preoperative radiotherapy varies widely. In this study, we aimed to identify novel biomarkers that could predict the response of colorectal tumors to treatment using a systems biology approach. We applied the Weighted Gene Co-Expression Network Analysis to construct co-expression networks and evaluated the correlation of these networks with radiation using the module-trait relationship. We then identified hub genes and related transcription factors in the selected co-expression module. Our analysis of seven constructed modules revealed that one module, which contained 113 nodes and 6066 edges, had the strongest correlation with radiation effects on CRC (correlation = 0.85; p-value = 6e-7). By analyzing the selected module with the CytoHubba plugin, we identified four hub genes, including ZEB2, JAM2, NDN, and PPAP2A. We also identified seven important transcription factors, including KLF4, SUZ12, TCF4, NANOG, POU5F1, SOX2, and SMARCA4, which may play essential roles in regulating the four hub genes. In summary, our findings suggest that ZEB2, JAM2, NDN, and PPAP2A, along with the seven transcription factors related to these hub genes, may be associated with the response of colorectal tumors to chemoradiotherapy.

Identification of Novel Biomarkers for Response to Preoperative Chemoradiation in Locally Advanced Rectal Cancer with Genetic Algorithm-Based Gene Selection.

BACKGROUND: The conventional treatment for patients with locally advanced colorectal tumors is preoperative chemo-radiotherapy (PCRT) preceding surgery. This treatment strategy has some long-term side effects, and some patients do not respond to it. Therefore, an evaluation of biomarkers that may help predict patients' response to PCRT is essential. METHODS: We took advantage of genetic algorithm to search the space of possible combinations of features to choose subsets of genes that would yield convenient performance in differentiating PCRT responders from non-responders using a logistic regression model as our classifier. RESULTS: We developed two gene signatures; first, to achieve the maximum prediction accuracy, the algorithm yielded 39 genes, and then, aiming to reduce the feature numbers as much as possible (while maintaining acceptable performance), a 5-gene signature was chosen. The performance of the two gene signatures was (accuracy = 0.97 and 0.81, sensitivity = 0.96 and 0.83, and specificity = 86 and 0.77) using a logistic regression classifier. Through analyzing bias and variance decomposition of the model error, we further investigated the involved genes by discovering and validating another 28-gene signature which possibly points towards two different sub-systems involved in the response of the patients to treatment. CONCLUSIONS: Using genetic algorithm as our gene selection method, we have identified two groups of genes that can differentiate PCRT responders from non-responders in patients of the studied dataset with considerable performance. IMPACT: After passing standard requirements, our gene signatures may be applicable as a robust and effective PCRT response prediction tool for colorectal cancer patients in clinical settings and may also help future studies aiming to further investigate involved pathways gain a clearer picture for the course of their research.