Document Type : Original Research

Authors

1 Department of Pathology, Faculty of Medicine, Menoufia University, Shibin Elkom, Egypt

2 Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Menoufia University, Shibin Elkom, Egypt

3 Department of Urology, Faculty of Medicine, Menoufia University, Shibin Elkom, Egypt

10.30699/ijp.2024.2017851.3227

Abstract

Background & Objective: Prostatic adenocarcinoma (PAC) is the second most prevalent cancer and the fifth leading cause of cancer death in men worldwide. Additionally, pathologists may face problems diagnosing it reliably and may need more than one marker. Thus, the search for new immunohistochemical biomarkers becomes mandatory. This study aims to investigate P4HB and SOX4 expression in prostatic carcinoma, their possible roles, and clinical significance.
Methods: This retrospective study included fifty-six cases of PAC and an equal number of nodular prostatic hyperplasia (NPH) that were immunohistochemically stained by P4HB and SOX4. The results of expression were compared between PAC and NPH cases, followed by correlations with available clinicopathological parameters.
Results: There was a highly significant difference between PAC and NPH regarding P4HB and SOX4 expressions in favor of PAC (both P<0.001). ROC curve analysis of the diagnostic power of P4HB showed 79% sensitivity, 76% specificity, 76.5%, and an area under the ROC curve of 0.845, while SOX4 showed (89%, 100%, and 0.946, respectively). P4HB and SOX4 expression showed a direct correlation (P<0.001). Moreover, SOX4 showed a significant inverse relation with ERG (P=0.047). There was a significant correlation between P4HB and SOX4 and Gleason score (P<0.001). Moreover, P4HB expression was significantly associated with lymphovascular invasion (P=0.013), while SOX4 expression showed a significant association with perineural invasion (P=0.05).
Conclusion: SOX4 and P4HB seem to have diagnostic and prognostic value in PAC. While there was a direct correlation between SOX4 and P4HB, an inverse relationship between SOX4 and ERG was detected.

Keywords

Main Subjects

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-49. [DOI:10.3322/caac.21660] [PMID]
  2. Sandhu S, Moore CM, Chiong E, Beltran H, Bristow RG, Williams SG. Prostate cancer. Lancet. 2021 Sep 18 [cited 2023 Aug 8];398(10305):1075-90. [DOI:10.1016/S0140-6736(21)00950-8] [PMID]
  3. Mokhtar N., Badawy O., Khorshed E., Mohamed G., Ibrahim M., Abdelazim H. Cancer Pathology Registry A 12-year Registry (2000-2011). Cairo. 2016.
  4. Desai MM, Cacciamani GE, Gill K, Zhang J, Liu L, Abreu A, et al. Trends in Incidence of Metastatic Prostate Cancer in the US. JAMA Netw Open. 2022 [cited 2023 Aug 30];5(3). [DOI:10.1001/jamanetworkopen.2022.2246] [PMID]
  5. Diamandis EP. Prostate-specific antigen: a cancer fighter and a valuable messenger? Clin Chem. 2000 Jul 1;46(7):896-900. [DOI:10.1093/clinchem/46.7.896] [PMID]
  6. Mashkoor FC, Al-Asadi JN, Al-Naama LM. Serum level of prostate-specific antigen (PSA) in women with breast cancer. Cancer Epidemiol. 2013 Oct 1;37(5):613-8. [DOI:10.1016/j.canep.2013.06.009] [PMID]
  7. Sirousbakht S, Rezakhaniha B. Effect of Colonoscopy on Prostate-Specific Antigen; New Words about an Old Subject. Int J Cancer Manag. 2018 11:7. 2018;11(7):68919. [DOI:10.5812/ijcm.68919]
  8. Pérez-Ibave DC, Burciaga-Flores CH, Elizondo-Riojas MÁ. Prostate-specific antigen (PSA) as a possible biomarker in non-prostatic cancer: A review. Cancer Epidemiol. 2018;54:48-55. [DOI:10.1016/j.canep.2018.03.009] [PMID]
  9. Rezakhaniha B, Arianpour N, Sirousbakht S. Effect of cystoscopy on prostate-specific antigen, new words about old subject. Iran J Cancer Prev. 2010;3(4):193-8.
  10. Jon Oxley, Murali Varma, Dan Berney. Standards and datasets for reporting cancers Dataset for histopathology reports for prostatic carcinoma June 2016. London; 2016.
  11. Zhu Z, He A, Lv T, Xu C, Lin L, Lin J. Overexpression of P4HB is correlated with poor prognosis in human clear cell renal cell carcinoma. Cancer Biomark. 2019;26(4):431-9. [DOI:10.3233/CBM-190450] [PMID]
  12. Wu Y, Peng Y, Guan B, He A, Yang K, He S, et al. P4HB: A novel diagnostic and prognostic biomarker for bladder carcinoma. Oncol Lett. 2021;21(2). [DOI:10.3892/ol.2020.12356] [PMID]
  13. Zhou Y, Yang J, Zhang Q, Xu Q, Lu L, Wang J, et al. P4HB knockdown induces human HT29 colon cancer cell apoptosis through the generation of reactive oxygen species and inactivation of STAT3 signaling. Mol Med Rep. 2019.19(1):231-7. [DOI:10.3892/mmr.2018.9660]
  14. Zhang J, Guo S, Wu Y, Zheng ZC, Wang Y, Zhao Y. P4HB, a Novel Hypoxia Target Gene Related to Gastric Cancer Invasion and Metastasis. Biomed Res Int. 2019;2019. [DOI:10.1155/2019/9749751] [PMID]
  15. Sun S, Lee D, Ho ASW, Pu JKS, Zhang XQ, Lee NP, et al. Inhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathways. Neuro Oncol. 2013 May;15(5):562-77. [DOI:10.1093/neuonc/not005] [PMID]
  16. Feng D, Li L, Li D, Wu R, Zhu W, Wang J, et al. Prolyl 4-hydroxylase subunit beta (P4HB) could serve as a prognostic and radiosensitivity biomarker for prostate cancer patients. Eur J Med Res. 2023;28(1). [DOI:10.1186/s40001-023-01215-2] [PMID]
  17. Cheung M, Abu-Elmagd M, Clevers H, Scotting PJ. Roles of Sox4 in central nervous system development. Molecular Brain Res. 2000;79(1-2):180-91. [DOI:10.1016/S0169-328X(00)00109-1] [PMID]
  18. Moreno CS. SOX4: The unappreciated oncogene. Semin Cancer Biol. 2020;67(Pt 1):57-64. [DOI:10.1016/j.semcancer.2019.08.027] [PMID]
  19. Vervoort SJ, Van Boxtel R, Coffer PJ. The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe? Oncogene. 2013.32(29):3397-409. [DOI:10.1038/onc.2012.506] [PMID]
  20. Kuwahara M, Yamashita M, Shinoda K, Tofukuji S, Onodera A, Shinnakasu R, et al. The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-β and suppresses T(H)2 differentiation. Nat Immunol. 2012;13(8):778-86. [DOI:10.1038/ni.2362] [PMID]
  21. Lai YH, Cheng J, Cheng D, Feasel ME, Beste KD, Peng J, et al. SOX4 interacts with plakoglobin in a Wnt3a-dependent manner in prostate cancer cells. BMC Cell Biol. 2011;12. [DOI:10.1186/1471-2121-12-50] [PMID]
  22. Bilir B, Osunkoya AO, Wiles WG, Sannigrahi S, Lefebvre V, Metzger D, et al. SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation. Cancer Res. 2016;76(5):1112-21. [DOI:10.1158/0008-5472.CAN-15-1868] [PMID]
  23. Yang W, Wu X, Zhou F. Collagen Type X Alpha 1 (COL10A1) Contributes to Cell Proliferation, Migration, and Invasion by Targeting Prolyl 4-Hydroxylase Beta Polypeptide (P4HB) in Breast Cancer. Med Sci Monit. 2021;27. [DOI:10.12659/MSM.928919] [PMID]
  24. Ma X, Wang J, Zhuang J, Ma X, Zheng N, Song Y, et al. P4HB modulates epithelial-mesenchymal transition and the β-catenin/Snail pathway influencing chemoresistance in liver cancer cells. Oncol Lett. 2020;20(1):257-65. [DOI:10.3892/ol.2020.11569] [PMID]
  25. Fedchenko N, Reifenrath J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue - a review. Diagn Pathol. 2014 [cited 2023 Nov 28];9:221. [DOI:10.1186/s13000-014-0221-9] [PMID]
  26. Dawoud MM, Aiad ASS, Bahbah AMNH, Shaban MI. Comparative study of immunohistochemical expression of ERG and MAGI2 in prostatic carcinoma. Ann Diagn Pathol. 2021 Jun 1 [cited 2023 Oct 16];52. [DOI:10.1016/j.anndiagpath.2021.151727] [PMID]
  27. Sekhoacha M, Riet K, Motloung P, Gumenku L, Adegoke A, Mashele S. Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches. Molecules. 2022;27(17). [DOI:10.3390/molecules27175730] [PMID]
  28. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo‐San Pedro JM, Cecconi F, et al. Molecular definitions of autophagy and related processes. EMBO J. 2017;36(13):1811-36. [DOI:10.15252/embj.201796697] [PMID]
  29. Yang Z, Ghoorun RA, Fan X, Wu P, Bai Y, Li J, et al. High expression of Beclin-1 predicts favorable prognosis for patients with colorectal cancer. Clin Res Hepatol Gastroenterol. 201539(1):98-106. [DOI:10.1016/j.clinre.2014.06.014] [PMID]
  30. Lai K, Killingsworth MC, Lee CS. The significance of autophagy in colorectal cancer pathogenesis and implications for therapy. J Clin Pathol. 2014;67(10):854-8. [DOI:10.1136/jclinpath-2014-202529] [PMID]
  31. Chen X, Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer. 2021;21(2):71-88. [DOI:10.1038/s41568-020-00312-2] [PMID]
  32. Pachikov AN, Gough RR, Christy CE, Morris ME, Casey CA, LaGrange CA, et al. The non-canonical mechanism of ER stress-mediated progression of prostate cancer. J Exp Clin Cancer Res. 2021;40(1).
  33. Luo B, Lee AS. The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene. 2013;17];32(7):805-18. DOI:10.1038/onc.2012.130] [PMID]
  34. Jin Y, Saatcioglu F. Targeting the Unfolded Protein Response in Hormone-Regulated Cancers. Trends Cancer. 2020.6(2):160-71. [DOI:10.1016/j.trecan.2019.12.001] [PMID]
  35. Bilir B, Osunkoya AO, Wiles WG, Sannigrahi S, Lefebvre V, Metzger D, et al. SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation. Cancer Res. 2016.76(5):1112-21. [DOI:10.1158/0008-5472.CAN-15-1868] [PMID]
  36. Beyer K, Moris L, Lardas M, Haire A, Barletta F, Scuderi S, et al. Diagnostic and prognostic factors in patients with prostate cancer: a systematic review. BMJ Open. 2022;12(4).
  37. Ma X, Wang J, Zhuang J, Ma X, Zheng N, Song Y, et al. P4HB modulates epithelial-mesenchymal transition and the β-catenin/Snail pathway influencing chemoresistance in liver cancer cells. Oncol Lett. 2020;20(1):257-65. [DOI:10.3892/ol.2020.11569] [PMID]
  38. Nieto MA, Huang RYYJ, Jackson RAA, Thiery JPP. EMT: 2016. Cell. 2016;166(1):21-45. [DOI:10.1016/j.cell.2016.06.028] [PMID]
  39. Hashemi M, Arani HZ, Orouei S, Fallah S, Ghorbani A, Khaledabadi M, et al. EMT mechanism in breast cancer metastasis and drug resistance: Revisiting molecular interactions and biological functions. Biomed Pharmacother. 2022;155. [DOI:10.1016/j.biopha.2022.113774] [PMID]
  40. Zong J, Guo C, Liu S, Sun MZ, Tang J. Proteomic research progress in lymphatic metastases of cancers. Clin Transl Oncol. 2012;14(1):21-30. [DOI:10.1007/s12094-012-0757-7] [PMID]
  41. Zhang J, Liang Q, Lei Y, Yao M, Li L, Gao X, et al. SOX4 induces epithelial-mesenchymal transition and contributes to breast cancer progression. Cancer Res. 2012;72(17):4597-608. [DOI:10.1158/0008-5472.CAN-12-1045] [PMID]
  42. Peng X, Liu G, Peng H, Chen A, Zha L, Wang Z. SOX4 contributes to TGF-β-induced epithelial-mesenchymal transition and stem cell characteristics of gastric cancer cells. Genes Dis. 2017;5(1):49-61. [DOI:10.1016/j.gendis.2017.12.005] [PMID]
  43. Shen H, Blijlevens M, Yang N, Frangou C, Wilson KE, Xu B, et al. Sox4 Expression Confers Bladder Cancer Stem Cell Properties and Predicts for Poor Patient Outcome. Int J Biol Sci. 2015;11(12):1363-75. [DOI:10.7150/ijbs.13240] [PMID]
  44. Dong H, Hu J, Wang L, Qi M, Lu N, Tan X, et al. SOX4 is activated by C-MYC in prostate cancer. Med Oncol. 2019;36(11). [DOI:10.1007/s12032-019-1317-6] [PMID]
  45. Fromont G, Godet J, Peyret A, Irani J, Celhay O, Rozet F, et al. 8q24 amplification is associated with Myc expression and prostate cancer progression and is an independent predictor of recurrence after radical prostatectomy. Hum Pathol. 2013;44(8):1617-23. / [DOI:10.1016/j.humpath.2013.01.012] [PMID]
  46. Sato H, Minei S, Hachiya T, Yoshida T, Takimoto Y. Fluorescence in situ hybridization analysis of c-myc amplification in stage TNM prostate cancer in Japanese patients. Int J Urol. 2006;13(6):761-6. [DOI:10.1111/j.1442-2042.2006.01399.x] [PMID]
  47. Liu Y, Zeng S, Jiang X, Lai D, Su Z. SOX4 induces tumor invasion by targeting EMT-related pathway in prostate cancer. Tumour Biol. 2017.39(5). [DOI:10.1177/1010428317694539] [PMID]
  48. Wang L, Zhang J, Yang X, Chang YWY, Qi M, Zhou Z, et al. SOX4 is associated with poor prognosis in prostate cancer and promotes epithelial-mesenchymal transition in vitro. Prostate Cancer Prostatic Dis. 2013;16(4):301-7. [DOI:10.1038/pcan.2013.25] [PMID]
  49. Arora K, Barbieri CE. Molecular Subtypes of Prostate Cancer. Curr Oncol Rep. 2018 Aug 1 [cited 2023 Nov 14];20(8). [DOI:10.1007/s11912-018-0707-9] [PMID]
  50. Wang L, Li Y, Yang X, Yuan H, Li X, Qi M, et al. ERG-SOX4 interaction promotes epithelial-mesenchymal transition in prostate cancer cells. Prostate. 2014;74(6):647-58. [DOI:10.1002/pros.22783] [PMID]
  51. Xu B, Chevarie-Davis M, Chevalier S, Scarlata E, Zeizafoun N, Dragomir A, et al. The prognostic role of ERG immunopositivity in prostatic acinar adenocarcinoma: a study including 454 cases and review of the literature. Hum Pathol. 2014;45(3):488-97. [DOI:10.1016/j.humpath.2013.10.012] [PMID]
  52. Ibrahim ASM, Hasan HAM, El-Sayed AMM. Immunohistochemical expression of ERG and P63 in some prostatic lesions. Egypt J Hosp Med. 2019;74(4):942-8. [DOI:10.21608/ejhm.2019.25563]