|
miR-155 rs767649 T>A gene polymorphism is associated with downregulation of miR-155 expression, suppressor of cytokine signaling-1 overexpression, and low probability of metastatic tumor at the time of breast cancer diagnosis
Sara Iranparast1, Maryam Tahmasebi-Birgani2, Azim Motamedfar3, Afshin Amari4, Mehri Ghafourian5
1 Department of Immunology, School of Medicine; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2 Department of Medical Genetics, School of Medicine; Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
3 Assistant professor of Radiology and Fellowship of Interventional Radiology, School of Medicine; Department of Radiology, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
4 Department of Immunology, School of Medicine; Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
5 Department of Immunology, School of Medicine; Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| Date of Submission | 30-Oct-2021 |
| Date of Decision | 20-Sep-2022 |
| Date of Acceptance | 27-Feb-2023 |
| Date of Web Publication | 20-Apr-2023 |
Correspondence Address:
Dr. Maryam Tahmasebi-Birgani
Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz
Iran
Prof. Mehri Ghafourian
Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Golestan Blvd, P.O. Box 6135715794, Ahvaz
Iran
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jrms.jrms_960_21
Background: MicroRNA-155 is a key player in inflammatory reactions, carcinogenesis, and tumor development. In this study, polymorphism of miRNA-155 rs767649 T>A and its gene and suppressor of cytokine signaling-1 (SOCS-1) expression were investigated in relation to cancer susceptibility and development in breast cancer (BC) patients. Materials and Methods: Polymorphism of miRNA-155 rs767649 T>A was evaluated between a population of 174 patients with BC and 129 controls using restriction fragment length polymorphism and the expression of miR-155 and SOCS-1 were examined in peripheral blood mononuclear cells (PBMCs) by real-time polymerase chain reaction. Results: TT genotype of miR-155 rs767649 T>A was associated with higher level of miR-155 in PBMCs of BC patients relative to AT and AA genotypes (21.76 ± 4.4, 4.046 ± 1.35, 2.56 ± 0.81, respectively; P < 0.001) and increased lymph node metastasis (r = 0.292, P = 0.001), not BC susceptibility (P = 0.402 and P = 0.535; respectively). TT genotype of miR-155 rs767649 T>A was associated with less gene expression of SOCS-1 in PBMCs of BC patients compared to AT and AA genotypes (1.173 ± 0.57, 0.92 ± 0.827, 5.512 ± 0.92, respectively; P = 0.003). Conclusion: This study demonstrated for the first time the association between the T allele of the rs767649 T>A polymorphism in the pre-MIR155 gene and higher expression of miR-155, lower expression of SOCS-1, and swift latent progression in newly diagnosed BC patients. Thus, miR-155 may play a critical role in BC pathogenesis.
Keywords: Breast cancer, expression, metastasis, miR-155, polymorphism
How to cite this article:
Iranparast S, Tahmasebi-Birgani M, Motamedfar A, Amari A, Ghafourian M. miR-155 rs767649 T>A gene polymorphism is associated with downregulation of miR-155 expression, suppressor of cytokine signaling-1 overexpression, and low probability of metastatic tumor at the time of breast cancer diagnosis. J Res Med Sci 2023;28:32 |
How to cite this URL:
Iranparast S, Tahmasebi-Birgani M, Motamedfar A, Amari A, Ghafourian M. miR-155 rs767649 T>A gene polymorphism is associated with downregulation of miR-155 expression, suppressor of cytokine signaling-1 overexpression, and low probability of metastatic tumor at the time of breast cancer diagnosis. J Res Med Sci [serial online] 2023 [cited 2023 Jun 4];28:32. Available from: https://www.jmsjournal.net/text.asp?2023/28/1/32/374403 |
*Maryam Tahmasebi.Birgani and Mehri Ghafourian equally correspond to this study, however, Mehri Ghafourian is the main correspondence.
| Introduction | |  |
Breast cancer (BC) is the most common cancer in women worldwide with high mortality.[1],[2] Despite various therapeutic plans, due to the progressive course of the disease, there is a possibility of incomplete eradication of malignant breast masses, so researchers are trying to discover new molecules, such as small transcript microRNAs (miRs), to provide additional therapeutic targeting to optimize detection and treatment methods.[3]
Recently, microRNAs (miRs) have gained attention in the initiation and progression of BC. These small noncoding RNAs regulate a variety of molecular pathways including cell cycle, differentiation, apoptosis, and metabolism.[4] Hence, it is not surprising their altered expressions may be connected with tumorigenesis.[5],[6] MicroRNA-155, introduced as an oncomiR, is over-expressed in BC patients.[7] It has been well documented that the functional polymorphisms in miRs are the most common form of variation present in the human genome and could affect cancer susceptibility and prognosis.[8],[9] However, until now, the role of polymorphisms within noncoding regions of miR-155 on BC susceptibility remains unknown. Some studies have implied that polymorphisms in miRs may influence the expression of mature miRs by modulating their structure and expression, reflecting the diversities of the susceptible factors for different tumors.[10]
Like other genes, miR-155 regulates its various target genes by binding to their 3′ untranslated regions. The suppressor of cytokine signaling-1 (SOCS-1) is one of the miR-155's target genes and an essential tumor-suppressor gene that is involved in cytokine signaling and cell proliferation. It has been evidenced that miRNA-155 negatively regulates the expression of the SOCS-1 gene and thereby promotes tumor invasion.[11],[12] SOCS-1 gene is the most potent member of the SOCS family that is cytokine-inducible negative regulators of cytokine signaling.[13]
The rs767649 T>A polymorphism in the promoter of miR-155 was reported in many diseases such as lung cancer,[14] cervical cancer (CC),[15] and hepatocellular carcinoma (HCC).[16] We hypothesize that functional polymorphism rs767649 T>A located in the flanking region of the miR-155 gene may contribute to the changes in the expression of miR-155 and SOCS-1, as well the development of BC. Thus, this study aimed to identify an efficient biomarker for screening and monitoring patients with newly diagnosed BC (NDBCs).
| Materials and Methods | | |
Patients
This study was performed on 174 patients with NDBC (aged 50.49 ± 12.08 years) recruited from the center of sonography and radiology, Ahvaz, Iran between December 2019 and January 2021. One 129 age-matched healthy controls (51 ± 10.50 years) with a negative history of BC were also enrolled. All subjects gave written informed consent. The inclusion criteria were based on clinical observation, positive family history of BC, breast imaging, and pathological examinations. Excluded subjects were individuals with unrelated pathologic results. All procedures performed in studies involving human participants were in accordance with the ethical standards of Ahvaz Jundishapur University of Medical Sciences (Grant No. CMRC-9814 and code of ethics: IR.AJUMS.REC.1398.690).
Genotyping
Genomic DNA was isolated from peripheral blood using a DNA extraction kit (DNJia Kit, Yazd, Iran) according to the manufacturer's instructions. Specific Single nucleotide polymorphisms (SNPs) were genotyped by restriction fragment length polymorphism (RFLP)-polymerase chain reaction (PCR). The PCR is programmed as follows: initial denaturation at 95°C for 10 min, 40 cycles of denaturation at 95°C for 35 s, annealing at 56°C for 35 s and extension at 72°C for 35 s and a final extension at 72°C for 5 min. To identify the miR-155 A/T polymorphism, the PCR product was digested with the restriction enzyme TSP45I (Thermo Fisher, USA, REF: ER1511). The pattern of RFLP was analyzed through 2% agarose gel electrophoresis [Figure 1]. | Figure 1: The miR-155 PCR product and its genotypes. Lane 1 shows the AA genotype (bands at 252 and 42bp); lanes 3, 4, 5, and 7 show the TT genotype (bands: 158, 94, and 42bp); lanes 2 and 6 show the AT genotype (bands at 252, 158, 94, 42bp); lane 8 shows uncut PCR product at 294bp; and lane 9 is the DNA ladder-50bp. PCR = Polymerase chain reaction
Click here to view |
Isolation of peripheral blood mononuclear cells
Blood samples (5 ml) were obtained from all subjects and collected in Ethylenediaminetetraacetic acid-containing tubes. Peripheral blood mononuclear cells (PBMCs) were obtained from both BC patients and controls using Ficoll-Paque (Lymphodex, Inno-train, Germany) density gradient centrifugation.
Quantitative real-time polymerase chain reaction
Total RNA was extracted from (PBMC using 1 ml TRIzol (Thermo Fisher Scientific, Invitrogen, MA, USA) according to the manufacturer's protocol. The expression of miR-155 and U6 (reference gene) was analyzed using universal specific primer sets and BON-miR quantitative polymerase chain reaction Kit (Stem Cell Technology, Tehran, Iran) Two specific primers were used for U6 as follows: (Forward: 5'-TGCGGGTGCTCGCTTCGGCAGC-3'),(Reverse: 5'-GTCGTATCCAGTGCAGGGTCCGAGGTGCACTGGA TACGACAAAATATGGAAC-3) and miR-155 (Forward: 5'-ACACTCCAGCTGGGTTAATGCTAATCGTGAT-3')(Stem-loop-primer:5'-CTCAACTGGTGTCGTGGA GTCGGCAATTCAGTTG AGACCCCTAT-3'). Optimal reaction conditions included an initial denaturation step at 95°C for 2 min, 40 cycles at 95°C for 5 s, 60°C for 30 s, and a final extension step at 72°C for 10 min.
In silico analysis
In order to investigate the possible effects of the miR-155 in the tumor environment, the target genes of the microRNAs were selected at the miRTarBase, mimiRNA, and miRTargetLink Human databases. This study focused only on target genes involved in the immune system and SOCS-1 was selected as a key target gene involved in the regulation of cytokine signaling and cell proliferation.
Quantitative real-time polymerase chain reaction
The expression of SOCS-1 and glyceraldehyde 3-phosphate dehydrogenase (reference gene) was analyzed using universal specific primer sets and cDNA synthesis Kit (SinaClon, Tehran, Iran) Data were normalized based on GAPDH expression as the housekeeping control gene. The primers were as following: (GAPDH; Forward: 5-GTGAACCATGAGAAGTATGACAAC-3, Reverse: 5-CATGAGTCCTTCCACGATACC-3'); (SOCS-1; Forward: 5'-CTGGTGCGCGACAGCCG-3', Revers: 5'-ACGTAGTGCTCCAGCAGCTC-3') and RealQ Plus2x Master Mix Green with high ROX™ (Amplicon, Stenhuggervej, Denmark). Optimal reaction conditions included an initial denaturation step at 95°C for 15 min, 40 cycles at 95°C for 15 s, 60°C for 60 s, and a final extension step at 72°C for 10 min.
Statistical analysis
All statistical analysis was carried out using SPSS version 26.0 (SPSS Inc., Armonk, NY, USA). The differences in genotype distribution between patients and healthy controls were analyzed by the Chi-square test. The representativeness of the subjects in the current study was evaluated using the Hardy–Weinberg equilibrium (HWE). The difference in gene expressions of miR-155 and SOCS-1 was assessed by Mann–Whitney U and Kruskal–Walis tests. P ≤0.05 were considered statistically significant.
| Results | | |
miR-155 rs767649 T>A polymorphism is not associated with breast cancer risk
Genotype frequency of miR-155 rs767649 T>A in BC patients is summarized in [Table 1] and compared with normal counterparts. As indicated TT was a common genotype among BC patients. The same pattern was observed for the control group and no significant difference was observed with the case group (P = 0.402 and 0.535–0.592 for alleles and genotypes, respectively) [Table 1]. Distribution of the rs767649 T>A genotypes in both the patient (χ2 = 0.173, P = 0.677) and the control (χ2 = 2.842, P = 0.0.091) groups by HWE which indicates randomness of both the patient and control samples. | Table 1: Genotypic and allelic frequencies of miR-155 rs767649 T>A polymorphisms in newly diagnosed breast cancer and control subjects
Click here to view |
miR-155 was overexpressed in breast cancer compared with normal ones
As shown in [Figure 2]a, miR-155 was markedly expressed in PBMCs of BC patients and the expression level was significantly more than the observed values for control individuals (6.42 ± 2.17 vs. 1.56 ± 0.47; respectively, P = 0.006) (Fold change: 4.11 ± 1.4). Additionally, our data indicated that there is a significant discrepancy in the miR-155 levels of PBMC between TT compared to AT, and AA genotypes (21.76 ± 4.4, 4.046 ± 1.35, 2.56 ± 0.81, respectively; P < 0.001) (Fold change AA vs. TT: 0.12 ± 0.037) (Fold change AT vs. TT: 0.185 ± 0.062). The miR-155 expression was significantly overexpressed in BC patients with the A allele as compared without the A allele (2.87 ± 0.69 vs. 21.76 ± 4.40; P = 0.019) (Fold change A + vs. A−: 0.134 ± 0.032) [Figure 2]b and [Figure 2]c. | Figure 2: Comparing the expression level of miR-155 in breast cancer patients. A comparison of the expression level of miR-155 in breast cancer patients and control (a). A comparing the miR-155 expression in NDBC patients with different variants of rs767649 T>A miR-155 (b). and also with and without A allele (c). NDBC = Newly diagnosed breast cancer. The ** indicates the P-value less than 0.01. The *** indicates the P-value less than 0.001
Click here to view |
Investigation of miRNA–mRNA interactions network
Common miRNA-target pairs deserved more attention due to their prominent role of them in the immune responses. The network consisted of 21 target genes that SOCS-1 was selected to evaluate in the present study.
The expression level of suppressor of cytokine signaling-1 decreased in breast cancer compared with normal ones
As shown in [Figure 3]a, SOCS-1 was markedly reduced in PBMCs of BC patients and the expression level was significantly less than the observed values for control individuals (3.082 ± 0.50 vs. 7.862 ± 1.40; respectively, P = 0.006) (Fold change: 0.326 ± 0.06). Additionally, our data indicated that there is a significant reduction in the SOCS-1 levels of PBMC between TT relative to AT and AA genotypes (1.173 ± 0.57, 0.92 ± 0.827, 5.512 ± 0.92, respectively; P = 0.003) (Fold change AA vs. TT: 4.69 ± 0.78) (Fold change AT vs. TT: 0.74 ± 0.7). Besides, SOCS-1 expression was no significant difference in BC patients with A allele as compared without A allele (4.21 ± 0.75, 1.17 ± 0.57, respectively; P = 0.248) (Fold change A + vs. A−: 4.06 ± 0.71) [Figure 3]b and [Figure 3]c. However, there was a significant negative correlation between the expression level of miR-155 and SOCS-1 (r = −0.234, P = 0.032). | Figure 3: Comparing the expression level of SOCS-1 in breast cancer patients. A comparison of the expression level of SOCS-1 in breast cancer patients and control (a). A comparing the SOCS-1 expression in NDBC patients with different variants of rs767649 T>A miR-155 (b). and also with and without A allele (c). SOCS-1 = Suppressor of cytokine signaling-1, NDBC = Newly diagnosed breast cancer, NS = Nonsigficance. The ** indicates the P-value less than 0.01
Click here to view |
Stratified analysis of the association between rs767649 T>A and breast cancer risk by demographic and clinical variables
The relationship between rs767649 T>A and invasion of BC was also evaluated. As mentioned in [Table 2], A allele frequency in miR-155 rs767649 T>A variants was significantly associated with lower levels of lymph node metastasis (r = 0.261, P = 0.001) and lower grade of tumor (r = 0.520, P < 0.001) at diagnosis time of NDBC patients in comparison patients without A allele. However, the same data were obtained for a higher Probability of lymph node metastasis and the grade of the tumor was observed in the BC patients studied with the TT genotype, compared to the AA and AT genotypes (r = 0.292, P = 0.001, and r = 0.734, P < 0.001; respectively) [Table 2]. By the way, our analyses showed that the TT was significantly associated with grade III BC, whilst the AT and AA genotypes were observed in patients with grade I and II BC (P < 0.001), implying that the protective effect of the AA genotype in miR-155 rs767649 T>A on BC risk was exerted mainly among the early stage of patients. Altogether, lacking A allele and TT genotype of the rs767649 T>A polymorphism in the pre-MIR155 gene was independently associated with swift latent progression in patients with NDBC. | Table 2: The association between alleles and variants frequency of miR-155 rs767649 T>A and the demographic data and clinicopathological presentation of breast cancer patients
Click here to view |
| Discussion | | |
The association between SNP of genes and the risk of BC has been generating great interest in the scientific community. Rs767649 T>A polymorphism of miR-155 located in the promoter of miR-155 has recently been investigated in different diseases[11],[12],[13] and for the first time, we searched its role in BC. In this study, we showed that TT is a common genotype in Iranian NDBC patients and control subjects; our result in this step was in line with the previous studies accomplished on several cancers in Iran and china.[14],[15],[16] Additionally, we investigated the association between miR-155 expression, its functional variant rs767649 T>A, cancer susceptibility, and cancer development in the Iranian population using a case-control design. Consistent with our hypotheses, our findings suggested that the functional variant rs767649 T>A of miR-155 located in the regulation region was associated with the swift progression of BC, although there was no association between miR-155 rs767649 T>A and BC susceptibility in patients with BC of Iran compared with healthy women. Our results demonstrated although there is no correlation between the presence of either A or T alleles and the susceptibility to BC, the type of allele expressed of miR-155 can be correlated with the expression levels of this small transcript and some clinicopathology characteristics of BC. Whilst, to date, only three studies have analyzed the association between miR-155 rs767649 T>A polymorphisms and the prognostic outcomes in various carcinomas,[15],[16] however, none of them has been performed on BC patients. One of them propounds a hypothesis that the T allele of rs767649 T>A contributes to the higher risk of HCC.[16] Another in vitro study on CC suggests that the transition of the A to T allele might be a causal variant for CC susceptibility through miR-155 downregulation at the transcriptional level.[15] Meanwhile, a recent study highlighted the risk of NSCLC susceptibility influenced by the A allele.[14]
In our study, the analyses of miR-155 expression showed its diagnostic value to differentiate BC patients from healthy controls. In addition, there were significant differences between different genotypes regarding miR-155 expression level in BC with a high level in TT genotype, as well as lacking A allele. Furthermore, we found that lacking the A allele is associated with an increased expression of miR-155 in PBMC of BC patients as well with more severe clinical manifestations (higher frequency of lymph node metastasis and higher grade of tumor). Therefore, due to the same frequency of variant TT in BC patients and healthy groups and the significant increase of the expression level of miR-155 in the patients, especially variant TT, another factor may have affected the change in miR-155 expression that is present in the tumor environment, not in healthy individuals. The results of the current study may be explained by previous studies which indicated that TT genotype and T allele in miR-155 rs767649 T>A were associated with increased risk of HCC, respectively, and T allele in miR-155 rs767649 T>A contributed to the higher expression level of miR-155 in HCC tissues.[16],[17] Moreover, Chernyy et al. showed evidence that miR-155 can be defined as molecular markers in regards to BC patients to prognosticate spread to the lymph node.[18] Nina Petrović et al. observed that miR-155 is predominately involved in the early stages of BC formation as well as in tumor spreading to the lymph nodes and that it might be effective for the screening of potential micrometastases that are not detectable with standard diagnostic procedures.[19]
The present study showed that SOCS-1 significantly decrease in patients compared with the controls, whilst the expression level of miR-155 was elevated in the BC patients. Besides, we observed a significant reduction of SOCS-1 expression in patients with either TT variant compared to the other genotypes, AT and AA. However, a significant negative correlation was observed between the expression level of miR-155 and SOCS-1. Previous studies have shown that the reduction in SOCS-1 mRNA, especially in high-grade patients, is associated with adverse clinical outcomes and poor prognosis in BC;[20],[21] our results suggest that this reduction may be influenced by miR-155.
| Conclusion | | |
The levels of miR-155 in PBMC were higher, especially in BC with TT genotype. In addition, the wild variant, TT, was associated with less gene expression of SOCS-1 known as a key tumor suppressor. Therefore, the rs767649 T>A polymorphism was associated with different levels of miR-155 and SOCS-1 in PBMC of NDBC. On the other hand, the wild genotype of SNP of miR-155 investigated in the current study was associated with the hidden progression of BC, higher grade of tumor, and faster lymph node metastasis, not susceptibility to BC and this knowledge may promote our understanding of the molecular mechanisms underlying the pathogenesis and progression of BC and in the development of improved therapies for the treatment of BC. Due to the same frequency of variant TT in BC patients and healthy groups and the significant increase of the expression level of miR-155 in the patients, especially variant TT, another factor may have affected the change in miR-155 expression that is present in the tumor environment, not in healthy individuals. Taken together, these novel findings may be clinically significant and highlight the role of miR-155 in the pathogenesis of BC, with possible therapeutic implications.
Acknowledgments
This study is part of a Ph.D. thesis by Sara Iranparast. Financial support by the Vice-Chancellor in Research Affairs and Cancer Research Center, at Ahvaz Jundishapur University of Medical Sciences, is gratefully acknowledged (Grant No. CMRC-9814 and code of ethics: IR.AJUMS.REC.1398.690). The creators are appreciative to the staff of the Cellular and Molecular Research Center of Ahvaz Jundishapur University of Medical Sciences for their cooperation and the specialists of the pathology unit of in Doctor Matourian Laboratory and Pars Laboratory in Ahvaz for their participation. The authors also thank all the subjects for their participation in this research.
Financial support and sponsorship
This study was financially supported by Research deputy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  |
| 2. | Fidler MM, Bray F, Soerjomataram I. The global cancer burden and human development: A review. Scand J Public Health 2018;46:27-36. |
| 3. | McGuire A, Brown JA, Kerin MJ. Metastatic breast cancer: The potential of miRNA for diagnosis and treatment monitoring. Cancer Metastasis Rev 2015;34:145-55. |
| 4. | Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004;116:281-97. |
| 5. | Guessous F, Zhang Y, Abounader R. The rising world of micrornas: Oncogenes and tumor suppressors in cancer. Front in Sci and Eng 2019;8:19-29. |
| 6. | Kim J, Yao F, Xiao Z, Sun Y, Ma L. MicroRNAs and metastasis: Small RNAs play big roles. Cancer Metastasis Rev 2018;37:5-15. |
| 7. | Chen J, Wang BC, Tang JH. Clinical significance of microRNA-155 expression in human breast cancer. J Surg Oncol 2012;106:260-6. |
| 8. | Srivastava K, Srivastava A. Comprehensive review of genetic association studies and meta-analyses on miRNA polymorphisms and cancer risk. PLoS One 2012;7:e50966. |
| 9. | Wang S, Tao G, Wu D, Zhu H, Gao Y, Tan Y, et al. A functional polymorphism in MIR196A2 is associated with risk and prognosis of gastric cancer. Mol Carcinog 2013;52 Suppl 1:E87-95. |
| 10. | Ren YG, Zhou XM, Cui ZG, Hou G. Effects of common polymorphisms in miR-146a and miR-196a2 on lung cancer susceptibility: A meta-analysis. J Thorac Dis 2016;8:1297-305. |
| 11. | Jiang M, Zhang WW, Liu P, Yu W, Liu T, Yu J. Dysregulation of SOCS-mediated negative feedback of cytokine signaling in carcinogenesis and its significance in cancer treatment. Front Immunol 2017;8:70. |
| 12. | Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, Merck E, et al. MicroRNA-155 is required for effector CD8+T cell responses to virus infection and cancer. Immunity 2013;38:742-53. |
| 13. | Yoshimura A, Ito M, Chikuma S, Akanuma T, Nakatsukasa H. Negative regulation of cytokine signaling in immunity. Cold Spring Harb Perspect Biol 2018;10:a028571. |
| 14. | Dezfuli NK, Adcock IM, Alipoor SD, Seyfi S, Salimi B, Mafi Golchin M, et al. The miR-146a SNP Rs2910164 and miR-155 SNP rs767649 are risk factors for non small cell lung cancer in the Iranian population. Can Respir J 2020; p. 1-15. |
| 15. | Wang S, Cao X, Ding B, Chen J, Cui M, Xu Y, et al. The rs767649 polymorphism in the promoter of miR-155 contributes to the decreased risk for cervical cancer in a Chinese population. Gene 2016;595:109-14. |
| 16. | Ji J, Xu M, Tu J, Zhao Z, Gao J, Chen M, et al. MiR-155 and its functional variant rs767649 contribute to the susceptibility and survival of hepatocellular carcinoma. Oncotarget 2016;7:60303-9. |
| 17. | Xie K, Ma H, Liang C, Wang C, Qin N, Shen W, et al. A functional variant in miR-155 regulation region contributes to lung cancer risk and survival. Oncotarget 2015;6:42781-92. |
| 18. | Chernyy V, Pustylnyak V, Kozlov V, Gulyaeva L. Increased expression of miR-155 and miR-222 is associated with lymph node positive status. J Cancer 2018;9:135-40. |
| 19. | Petrović N, Kolaković A, Stanković A, Lukić S, Řami A, Ivković M, et al. MiR-155 expression level changes might be associated with initial phases of breast cancer pathogenesis and lymph-node metastasis. Cancer Biomark 2016;16:385-94. |
| 20. | Ghafouri-Fard S, Oskooei VK, Azari I, Taheri M. Suppressor of cytokine signaling (SOCS) genes are downregulated in breast cancer. World J Surg Oncol 2018;16:226. |
| 21. | Smolkova B, Mego M, Horvathova Kajabova V, Cierna Z, Danihel L, Sedlackova T, et al. Expression of SOCS1 and CXCL12 proteins in primary breast cancer are associated with presence of circulating tumor cells in peripheral blood. Transl Oncol 2016;9:184-90. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
|
Search Pubmed for