Expression and Prognostic Value of RAD51 in Adenocarcinoma at the Gastroesophageal Junction
-
Darebai Redati
,
Xinhui Yang
,
Cheng Lei
,
Lin Liu
,
Lei Ge
,
Haijiang Wang
Abstract
Background: The RAD51 recombinase is involved in homologous recombination and DNA repair. However, the association of RAD51 with the prognosis of adenocarcinoma at the gastroesophageal junction (ACGEJ) is not clear. We aimed to investigate the association of RAD51 with ACGEJ prognosis.
Methods: The difference in the expression level of RAD51 between ACGEJ tumors and control tissues in the microarray datasets (GSE159721, GSE74553, and GSE96669) were compared. The online Kaplan-Meier plotter survival analysis and meta-analysis were used to analyze the association of RAD51 with overall survival in pan-cancers. MiRNAs targeting RAD51 were identified and their expression profiles in ACGEJ tumors were analyzed. Functional enrichment analysis was performed for miRNAs of RAD51.
Results: RAD51 was upregulated in ACGEJ tumors compared with control tissues (P < 0.05). High RAD51 level was correlated with a poor prognosis in stomach adenocarcinoma and esophageal cancer. The meta-analysis showed that high RAD51 level was correlated with a poor prognosis in TCGA pan-cancers (P = 0.03). Six regulatory miRNAs of RAD51, including hsa-miR-182, hsa-miR-221, and hsa-miR-34a, were downregulated in ACGEJ tumor tissues and were associated with pathways including “fatty acid biosynthesis” and “viral carcinogenesis”.
Conclusions: RAD51 is a potent prognostic biomarker in ACGEJ. MiRNAs including hsa-miR-182, hsa-miR-221, and hsa-miR-34a might play crucial roles in ACGEJ by regulating the RAD51 gene.
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12. Laurini E, Marson D, Fermeglia A, Aulic S, Fermeglia M, Pricl S (2020). Role of RAD51 and DNA repair in cancer: a mo-lecular perspective. Pharmacol Ther, 208:107492.
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14. Chen JJ, Silver D, Cantor S, Livingston DM, Scully R (1999). BRCA1, BRCA2, and RAD51 operate in a common DNA damage response pathway. Cancer Res, 59(7 Supplement):1752s-1756s.
15. Bishara LA, Machour FE, Awwad SW, Ay-oub N (2021). NELF complex fosters BRCA1 and RAD51 recruitment to DNA damage sites and modulates sensitivity to PARP inhibition. DNA Repair, 97:103025.
16. Kolinjivadi AM, Sannino V, de Antoni A, Técher H, Baldi G, Costanzo V (2017). Moonlighting at replication forks–a new life for homologous recombination pro-teins BRCA1, BRCA2 and RAD51. FEBS Lett, 591(8):1083-1100.
17. Kaplan AR, Gueble SE, Liu Y, et al (2019). Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51. Sci Transl Med, 11(492):eaav4508.
18. Tennstedt P, Fresow R, Simon R, et al (2013). RAD51 overexpression is a nega-tive prognostic marker for colorectal ad-enocarcinoma. Int J Cancer, 132(9):2118-2126.
19. Xu H, Xiong C, Chen Y, Zhang C, Bai D (2021). Identification of RAD51 as a prognostic biomarker correlated with immune infiltration in hepatocellular car-cinoma. Bioengineered, 12(1):2664-2675.
20. Söderlund K, Skoog L, Fornander T, Ask-malm MS (2007). The BRCA1/BRCA2/RAD51 complex is a prognostic and predictive factor in early breast cancer. Radiother Oncol, 84(3):242-251.
21. Li Y, Wang W-y, Xiao J-h, et al (2017). Overexpression of RAD51 predicts poor prognosis in colorectal cancer: our expe-rience with 54 patients. PloS One, 12(1):e0167868.
22. Xu Y, Chen K, Cai Y, Cheng C, Zhang Z, Xu G (2019). Overexpression of RAD51 predicts poor prognosis and silencing of RAD51 increases chemo-sensitivity to doxorubicin in neuroblastoma. Am J Transl Res, 11(9):5788.
23. Du L-Q, Wang Y, Wang H, Cao J, Liu Q, Fan F-Y (2011). Knockdown of RAD51 expression induces radiation-and chemo-sensitivity in osteosarcoma cells. Med On-col, 28(4):1481-1487.
24. Liu G, Xue F, Zhang W (2015). miR-506: a regulator of chemo-sensitivity through suppression of the RAD51-homologous recombination axis. Chin J Cancer, 34(3):1-3.
25. Zhang Z, Huo H, Liao K, et al (2018). RPA1 downregulation enhances nasopharyngeal cancer radiosensitivity via blocking RAD51 to the DNA damage site. Exp Cell Res, 371(2):330-341.
26. Liu S, Lin Z, Zheng Z, et al (2020). Serum exosomal microRNA-766-3p expression is associated with poor prognosis of esophageal squamous cell carcinoma. Cancer Sci, 111(10):3881-3892.
27. Zhang R, Pang B, Xin T, et al (2016). Plasma miR-221/222 family as novel descriptive and prognostic biomarkers for glioma. Mol Neurobiol, 53(3):1452-1460.
28. Guo J, Liu C, Wang W, et al (2018). Identifi-cation of serum miR-1915-3p and miR-455-3p as biomarkers for breast cancer. PloS One, 13(7):e0200716.
29. Liu H, Du L, Wen Z, et al (2013). Up-regulation of miR-182 expression in colo-rectal cancer tissues and its prognostic value. Int J Colorectal Dis, 28(5):697-703.
30. Yao X-G, Tan Q, Liu P-P, Feng L-J (2019). Tissue microRNA-182 expression level and its potential prognostic value for pa-pillary thyroid carcinoma. Int J Clin Exp Pathol, 12(8):3128–3133.
31. Rapti S-M, Kontos CK, Papadopoulos IN, Scorilas A (2014). Enhanced miR-182 transcription is a predictor of poor over-all survival in colorectal adenocarcinoma patients. Clin Chem Lab Med, 52(8):1217-1227.
32. Stenvold H, Donnem T, Andersen S, Al-Saad S, Busund L-T, Bremnes RM (2014). Stage and tissue-specific prognos-tic impact of miR-182 in NSCLC. BMC Cancer, 14(1):1-10.
33. Chen Y-Y, Ho H-L, Lin S-C, Ho TD-H, Hsu C-Y (2018). Upregulation of miR-125b, miR-181d, and miR-221 predicts poor prognosis in MGMT promoter-unmethylated glioblastoma patients. Am J Forensic Med Pathol, 149(5):412-417.
34. Yuan K, Xie K, Fox J, et al (2013). De-creased levels of miR-224 and the passen-ger strand of miR-221 increase MBD2, suppressing maspin and promoting colo-rectal tumor growth and metastasis in mice. Gastroenterology, 145(4):853-864. e859.
35. Chen A-H, Qin Y-E, Tang W-F, Tao J, Song H-m, Zuo M (2017). MiR-34a and miR-206 act as novel prognostic and therapy biomarkers in cervical cancer. Cancer Cell Int, 17(1):63.
36. Rapti S-M, Kontos CK, Christodoulou S, Papadopoulos IN, Scorilas A (2017). miR-34a overexpression predicts poor prog-nostic outcome in colorectal adenocarci-noma, independently of clinicopathologi-cal factors with established prognostic value. Clin Biochem, 50(16-17):918-924.
2. Eusebi LH, Telese A, Marasco G, Bazzoli F, Zagari RM (2020). Gastric cancer preven-tion strategies: a global perspective. J Gas-troenterol Hepatol, 35(9):1495-1502.
3. Buas MF, Vaughan TL (2013). Epidemiolo-gy and risk factors for gastroesophageal junction tumors: understanding the rising incidence of this disease. Semin Radiat On-col, 23(1):3-9.
4. Pedrazzani C, de Manzoni G, Marrelli D, et al (2007). Lymph node involvement in advanced gastroesophageal junction ade-nocarcinoma. J Thorac Cardiovasc Surg, 134(2):378-385.
5. Lai S, Su T, He X, Lin Z, Chen S (2018). Prognostic value of resected lymph nodes numbers for Siewert II gas-troesophageal junction cancer. Oncotarget, 9(2):2797-2809.
6. Janjigian Y, Werner D, Pauligk C, et al (2012). Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA In-ternational collaborative analysis. Ann On-col, 23(10):2656-2662.
7. Al-Batran S-E, Homann N, Pauligk C, et al (2017). Effect of neoadjuvant chemother-apy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction can-cer: the AIO-FLOT3 trial. JAMA Oncol, 3(9):1237-1244.
8. Kamarajah SK, Phillips AW, Griffiths EA, Ferri L, Hofstetter WL, Markar SR (2021). Esophagectomy or total gastrectomy for Siewert 2 gastroesophageal junction (GEJ) adenocarcinoma? A registry-based analysis. Ann Surg Oncol, 28(13):8485-8494.
9. Roy PS, Nyodu T, Hazarika M, et al (2019). Prevalence of HER2 expression and its correlation with clinicopathological pa-rameters in gastric or gastroesophageal junction adenocarcinoma in North-East Indian population. APJCP, 20(4):1139-1145.
10. Song D, Tian J, Hu Y, et al (2020). Identifi-cation of biomarkers associated with di-agnosis and prognosis of gastroesopha-geal junction adenocarcinoma–a study based on integrated bioinformatics analy-sis in GEO and TCGA database. Medi-cine, 99(51):e23605.
11. Odenthal M, Hee J, Gockel I, et al (2015). Serum micro RNA profiles as prognos-tic/predictive markers in the multimodali-ty therapy of locally advanced adenocar-cinomas of the gastroesophageal junc-tion. Int J Cancer, 137(1):230-237.
12. Laurini E, Marson D, Fermeglia A, Aulic S, Fermeglia M, Pricl S (2020). Role of RAD51 and DNA repair in cancer: a mo-lecular perspective. Pharmacol Ther, 208:107492.
13. Demeyer A, Benhelli-Mokrani H, Chenais B, Weigel P, Fleury F (2021). Inhibiting ho-mologous recombination by targeting RAD51 protein. Biochim Biophys Acta Rev Cancer, 1876(2):188597.
14. Chen JJ, Silver D, Cantor S, Livingston DM, Scully R (1999). BRCA1, BRCA2, and RAD51 operate in a common DNA damage response pathway. Cancer Res, 59(7 Supplement):1752s-1756s.
15. Bishara LA, Machour FE, Awwad SW, Ay-oub N (2021). NELF complex fosters BRCA1 and RAD51 recruitment to DNA damage sites and modulates sensitivity to PARP inhibition. DNA Repair, 97:103025.
16. Kolinjivadi AM, Sannino V, de Antoni A, Técher H, Baldi G, Costanzo V (2017). Moonlighting at replication forks–a new life for homologous recombination pro-teins BRCA1, BRCA2 and RAD51. FEBS Lett, 591(8):1083-1100.
17. Kaplan AR, Gueble SE, Liu Y, et al (2019). Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51. Sci Transl Med, 11(492):eaav4508.
18. Tennstedt P, Fresow R, Simon R, et al (2013). RAD51 overexpression is a nega-tive prognostic marker for colorectal ad-enocarcinoma. Int J Cancer, 132(9):2118-2126.
19. Xu H, Xiong C, Chen Y, Zhang C, Bai D (2021). Identification of RAD51 as a prognostic biomarker correlated with immune infiltration in hepatocellular car-cinoma. Bioengineered, 12(1):2664-2675.
20. Söderlund K, Skoog L, Fornander T, Ask-malm MS (2007). The BRCA1/BRCA2/RAD51 complex is a prognostic and predictive factor in early breast cancer. Radiother Oncol, 84(3):242-251.
21. Li Y, Wang W-y, Xiao J-h, et al (2017). Overexpression of RAD51 predicts poor prognosis in colorectal cancer: our expe-rience with 54 patients. PloS One, 12(1):e0167868.
22. Xu Y, Chen K, Cai Y, Cheng C, Zhang Z, Xu G (2019). Overexpression of RAD51 predicts poor prognosis and silencing of RAD51 increases chemo-sensitivity to doxorubicin in neuroblastoma. Am J Transl Res, 11(9):5788.
23. Du L-Q, Wang Y, Wang H, Cao J, Liu Q, Fan F-Y (2011). Knockdown of RAD51 expression induces radiation-and chemo-sensitivity in osteosarcoma cells. Med On-col, 28(4):1481-1487.
24. Liu G, Xue F, Zhang W (2015). miR-506: a regulator of chemo-sensitivity through suppression of the RAD51-homologous recombination axis. Chin J Cancer, 34(3):1-3.
25. Zhang Z, Huo H, Liao K, et al (2018). RPA1 downregulation enhances nasopharyngeal cancer radiosensitivity via blocking RAD51 to the DNA damage site. Exp Cell Res, 371(2):330-341.
26. Liu S, Lin Z, Zheng Z, et al (2020). Serum exosomal microRNA-766-3p expression is associated with poor prognosis of esophageal squamous cell carcinoma. Cancer Sci, 111(10):3881-3892.
27. Zhang R, Pang B, Xin T, et al (2016). Plasma miR-221/222 family as novel descriptive and prognostic biomarkers for glioma. Mol Neurobiol, 53(3):1452-1460.
28. Guo J, Liu C, Wang W, et al (2018). Identifi-cation of serum miR-1915-3p and miR-455-3p as biomarkers for breast cancer. PloS One, 13(7):e0200716.
29. Liu H, Du L, Wen Z, et al (2013). Up-regulation of miR-182 expression in colo-rectal cancer tissues and its prognostic value. Int J Colorectal Dis, 28(5):697-703.
30. Yao X-G, Tan Q, Liu P-P, Feng L-J (2019). Tissue microRNA-182 expression level and its potential prognostic value for pa-pillary thyroid carcinoma. Int J Clin Exp Pathol, 12(8):3128–3133.
31. Rapti S-M, Kontos CK, Papadopoulos IN, Scorilas A (2014). Enhanced miR-182 transcription is a predictor of poor over-all survival in colorectal adenocarcinoma patients. Clin Chem Lab Med, 52(8):1217-1227.
32. Stenvold H, Donnem T, Andersen S, Al-Saad S, Busund L-T, Bremnes RM (2014). Stage and tissue-specific prognos-tic impact of miR-182 in NSCLC. BMC Cancer, 14(1):1-10.
33. Chen Y-Y, Ho H-L, Lin S-C, Ho TD-H, Hsu C-Y (2018). Upregulation of miR-125b, miR-181d, and miR-221 predicts poor prognosis in MGMT promoter-unmethylated glioblastoma patients. Am J Forensic Med Pathol, 149(5):412-417.
34. Yuan K, Xie K, Fox J, et al (2013). De-creased levels of miR-224 and the passen-ger strand of miR-221 increase MBD2, suppressing maspin and promoting colo-rectal tumor growth and metastasis in mice. Gastroenterology, 145(4):853-864. e859.
35. Chen A-H, Qin Y-E, Tang W-F, Tao J, Song H-m, Zuo M (2017). MiR-34a and miR-206 act as novel prognostic and therapy biomarkers in cervical cancer. Cancer Cell Int, 17(1):63.
36. Rapti S-M, Kontos CK, Christodoulou S, Papadopoulos IN, Scorilas A (2017). miR-34a overexpression predicts poor prog-nostic outcome in colorectal adenocarci-noma, independently of clinicopathologi-cal factors with established prognostic value. Clin Biochem, 50(16-17):918-924.
| Files | ||
| Issue | Vol 51 No 10 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v51i10.10981 | |
| Keywords | ||
| Gastroesophageal junction adenocarcinoma RAD51 recombinase microRNAs The Cancer Genome Atlas | ||
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How to Cite
1.
Redati D, Yang X, Lei C, Liu L, Ge L, Wang H. Expression and Prognostic Value of RAD51 in Adenocarcinoma at the Gastroesophageal Junction. Iran J Public Health. 2022;51(10):2231-2243.
