Epidermal growth factor receptor’s role in the regulation of switching the molecular subtypes in prostate cancer

Sarathkumar Edachery; Sathisha Gonchigar Jayanna; Jayaprakash Shetty; Dhananjay B. Alagundagi; Prakash Patil; Shwetha Shetty Kalladka; Sudeep D. Ghate; Praveenkumar Shetty

doi:10.7324/JAPS.2025.225250

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Abstract

Epidermal growth factor receptor (EGFR) stands out to being a key player in promoting the progression to an invasive, metastatic state in prostate cancer (PCa). However, the precise molecular mechanisms regulating EGFR in relation to early detection and recurrence in advanced stages are still unclear. Thus, in the current study, we investigated the protein expression of EGFR in PCa patients and mouse tissue by immunohistochemistry and western blot technique using PCa cell lines. Relative expression of EGFR and its associated microRNAs (miRNAs) and circular RNAs (circRNAs) were investigated in PCa cell lines DU145 and LNCaP by real-time quantitative PCR and data were compared using a non-parametric t-test. In our study, we identified three up-regulated (hsa-miR-1199, hsa-miR-7110, and hsa-miR-6778) and four downregulated (miR-936, miR-1275/4665-5p, miR-423-5p, and miR-493-5p) EGFR binding miRNAs in metastatic PCa. Furthermore, circRNAs, of EGFR and its associated phospholipid-binding protein, Annexin A2, such as hsa_circ_0035565, hsa_circ_0080228, hsa_circ_0080221, and hsa_circ_0080222 were upregulated in metastatic PCa cell lines, while their targets miR-936, miR-1275/4665-5p, miR-423-5p, and miR-493-5p were downregulated. EGFR is essential in driving the advancement of PCa towards an invasive and metastasis. miRNAs associated with EGFR, with their corresponding circRNAs, might play a significant role in regulating the differential expression of EGFR in hormone-dependent and hormone-independent metastatic PCa.

Keyword: EGFR biomarker circular RNA micro-RNA prostate cancer

Citation:

Edachery S, Jayanna SG, Shetty J, Alagundagi DB, Patil P, Shetty KS, Ghate SD, Shetty P. Epidermal growth factor receptor’s role in the regulation of switching the molecular subtypes in prostate cancer. J Appl Pharm Sci. 2025. Online First. http://doi.org/10.7324/JAPS.2025.225250

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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2. Tao LJ, Pan XY, Wang JW, Zhang L, Tao LS, Liang CZ. Circular RNA circANKS1B acts as a sponge for miR-152-3p and promotes prostate cancer progression by upregulating TGF-α expression. Prostate. 2021;81(5):271-8. https://doi.org/10.1002/pros.24102
3. Bu T, Li L, Tian J. Unlocking the role of non-coding RNAs in prostate cancer progression: exploring the interplay with the Wnt signaling pathway. Front Pharmacol. 2023;14:1269233. https://doi.org/10.3389/fphar.2023.1269233
4. Cheng L, He Q, Liu B, Chen L, Lv F, Li X, et al. SGK2 promotes prostate cancer metastasis by inhibiting ferroptosis via upregulating GPX4. Cell Death Dis. 2023;14(1):74. https://doi.org/10.1038/s41419-023-05614-5
5. Caggia S, Johnston A, Walunj DT, Moore AR, Peer BH, Everett RW, et al. Gαi2 protein inhibition blocks chemotherapy-and anti-androgen-induced prostate cancer cell migration. Cancers. 2024;16(2):296. https://doi.org/10.3390/cancers16020296
6. Soares S, Aires F, Monteiro A, Pinto G, Faria I, Sales G, et al. Radiotherapy metastatic prostate cancer cell lines treated with gold nanorods modulate miRNA signatures. Int J Mol Sci. 2024;25(5):2754. https://doi.org/10.3390/ijms25052754
7. Nasta?y P, Stoupiec S, Pop?da M, Smentoch J, Schlomm T, Morrissey C, et al. EGFR as a stable marker of prostate cancer dissemination to bones. Br J Cancer. 2020;123(12):1767-74. https://doi.org/10.1038/s41416-020-01052-8
8. Edachery S, Patil P, Mohan R, Aradhya B, Shetty J, Kabekkodu SP, et al. Loss of miR-936 leads to acquisition of androgen-independent metastatic phenotype in prostate cancer. Sci Rep. 2022;12(1):17070. https://doi.org/10.1038/s41598-022-20777-5
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20. Shetty PK, Thamake SI, Biswas S, Johansson SL, Vishwanatha JK. Reciprocal regulation of annexin A2 and EGFR with Her-2 in Her-2 negative and herceptin-resistant breast cancer. PLoS One. 2012;7(9):e44299. https://doi.org/10.1371/journal.pone.0044299
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23. Carrion-Salip D, Panosa C, Menendez JA, Puig T, Oliveras G, Pandiella A, et al. Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands. Int J Oncol. 2012;41(3):1128-38. https://doi.org/10.3892/ijo.2012.1509
24. Sidorova EA, Zhernov YV, Antsupova MA, Khadzhieva KR, Izmailova AA, Kraskevich DA, et al. The role of different types of microRNA in the pathogenesis of breast and prostate cancer. Int J Mol Sci. 2023;24(3):1980. https://doi.org/10.3390/ijms24031980
25. Zhang P, Chen L, Zhou F, He Z, Wang G, Luo Y. NRP1 promotes prostate cancer progression via modulating EGFR-dependent AKT pathway activation. Cell Death Dis. 2023;14(2):159. https://doi.org/10.1038/s41419-023-05696-1
26. Höti N, Lih TS, Pan J, Zhou Y, Yang G, Deng A, et al. A comprehensive analysis of FUT8 overexpressing prostate cancer cells reveals the role of EGFR in castration resistance. Cancers. 2020;12(2):468. https://doi.org/10.3390/cancers12020468
27. Traish A, Morgentaler A. Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth. Br J Cancer. 2009;101(12):1949-56. https://doi.org/10.1038/sj.bjc.6605376
28. Inoue J, Inazawa J. Cancer-associated miRNAs and their therapeutic potential. J Hum Genet. 2021;66(9):937-45. https://doi.org/10.1038/s10038-021-00938-6
29. Palanichamy JK, Rao DS. miRNA dysregulation in cancer: towards a mechanistic understanding. Front Genet. 2014;5:54. https://doi.org/10.3389/fgene.2014.00054
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33. Fang Y, Gao W. Roles of microRNAs during prostatic tumorigenesis and tumor progression. Oncogene. 2014;33(2):135-47. https://doi.org/10.1038/onc.2013.54
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41. Diepenbruck M, Tiede S, Saxena M, Ivanek R, Kalathur RKR, Lüönd F, et al. miR-1199-5p and Zeb1 function in a double-negative feedback loop potentially coordinating EMT and tumour metastasis. Nat Commun. 2017;8(1):1168. https://doi.org/10.1038/s41467-017-01197-w
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1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-63. https://doi.org/10.3322/caac.21834

2. Tao LJ, Pan XY, Wang JW, Zhang L, Tao LS, Liang CZ. Circular RNA circANKS1B acts as a sponge for miR-152-3p and promotes prostate cancer progression by upregulating TGF-α expression. Prostate. 2021;81(5):271-8. https://doi.org/10.1002/pros.24102

3. Bu T, Li L, Tian J. Unlocking the role of non-coding RNAs in prostate cancer progression: exploring the interplay with the Wnt signaling pathway. Front Pharmacol. 2023;14:1269233. https://doi.org/10.3389/fphar.2023.1269233

4. Cheng L, He Q, Liu B, Chen L, Lv F, Li X, et al. SGK2 promotes prostate cancer metastasis by inhibiting ferroptosis via upregulating GPX4. Cell Death Dis. 2023;14(1):74. https://doi.org/10.1038/s41419-023-05614-5

5. Caggia S, Johnston A, Walunj DT, Moore AR, Peer BH, Everett RW, et al. Gαi2 protein inhibition blocks chemotherapy-and anti-androgen-induced prostate cancer cell migration. Cancers. 2024;16(2):296. https://doi.org/10.3390/cancers16020296

6. Soares S, Aires F, Monteiro A, Pinto G, Faria I, Sales G, et al. Radiotherapy metastatic prostate cancer cell lines treated with gold nanorods modulate miRNA signatures. Int J Mol Sci. 2024;25(5):2754. https://doi.org/10.3390/ijms25052754

7. Nasta?y P, Stoupiec S, Pop?da M, Smentoch J, Schlomm T, Morrissey C, et al. EGFR as a stable marker of prostate cancer dissemination to bones. Br J Cancer. 2020;123(12):1767-74. https://doi.org/10.1038/s41416-020-01052-8

8. Edachery S, Patil P, Mohan R, Aradhya B, Shetty J, Kabekkodu SP, et al. Loss of miR-936 leads to acquisition of androgen-independent metastatic phenotype in prostate cancer. Sci Rep. 2022;12(1):17070. https://doi.org/10.1038/s41598-022-20777-5

9. Sun C, Lu C, Li X, Li R, Wen Z, Ge Z, et al. The value of a panel of circulating microRNAs in screening prostate cancer. Transl Cancer Res. 2024;13(2):687. https://doi.org/10.21037/tcr-23-1313

10. Tseng JC, Wang BJ, Wang YP, Kuo YY, Chen JK, Hour TC, et al. Caffeic acid phenethyl ester suppresses EGFR/FAK/Akt signaling, migration, and tumor growth of prostate cancer cells. Phytomedicine. 2023;116:154860. https://doi.org/10.1016/j.phymed.2023.154860

11. Zhao P, Han P, Ma Y, Tian P, Li J. Circ_0082878 contributes to prostate cancer progression via the miR-455-3p/WTAP axis. Environ Toxicol. 2024;39(2):979-90. https://doi.org/10.1002/tox.24031

12. Xu W, Zhong Z, Gu L, Xiao Y, Chen B, Hu W. circCPA4 induces malignant behaviors of prostate cancer via miR-491-5p/SHOC2 feedback loop. Clinics. 2024;79:100314. https://doi.org/10.1016/j.clinsp.2023.100314

13. Ghamlouche F, Yehya A, Zeid Y, Fakhereddine H, Fawaz J, Liu YN, et al. MicroRNAs as clinical tools for diagnosis, prognosis, and therapy in prostate cancer. Transl Oncol. 2023;28:101613. https://doi.org/10.1016/j.tranon.2022.101613

14. Mazzetti S, Defeudis A, Nicoletti G, Chiorino G, De Luca S, Faletti R, et al. Development and validation of a clinical decision support system based on PSA, microRNAs, and MRI for the detection of prostate cancer. Eur Radiol. 2024;34(8):1-10. https://doi.org/10.1007/s00330-023-10542-1

15. Wu YP, Lin XD, Chen SH, Ke ZB, Lin F, Chen DN, et al. Identification of prostate cancer-related circular RNA through bioinformatics analysis. Front Genet. 2020;11:892. https://doi.org/10.3389/fgene.2020.00892

16. Wang X, Wang R, Wu Z, Bai P. Circular RNA ITCH suppressed prostate cancer progression by increasing HOXB13 expression via spongy miR-17-5p. Cancer Cell Int. 2019;19:1-11. https://doi.org/10.1186/s12935-019-0994-8

17. Choi S, Lee S, Han YH, Choi J, Kim I, Lee J, et al. miR-31-3p functions as a tumor suppressor by directly targeting GABBR2 in prostate cancer. Front Oncol. 2022;12:945057. https://doi.org/10.3389/fonc.2022.945057

18. Khan S, Jha A, Panda AC, Dixit A. Cancer-associated circRNA- miRNA-mRNA regulatory networks: a meta-analysis. Front Mol Biosci. 2021;8:671309. https://doi.org/10.3389/fmolb.2021.671309

19. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47(W1):W556-60. https://doi.org/10.1093/nar/gkz430

20. Shetty PK, Thamake SI, Biswas S, Johansson SL, Vishwanatha JK. Reciprocal regulation of annexin A2 and EGFR with Her-2 in Her-2 negative and herceptin-resistant breast cancer. PLoS One. 2012;7(9):e44299. https://doi.org/10.1371/journal.pone.0044299

21. Xin S, Liu X, Li Z, Sun X, Wang R, Zhang Z, et al. ScRNA-seq revealed an immunosuppression state and tumor microenvironment heterogeneity related to lymph node metastasis in prostate cancer. Exp Hematol Oncol. 2023;12(1):49. https://doi.org/10.1186/s40164-023-00407-0

22. Cussenot O, Valeri A, Berthon P, Fournier G, Mangin P. Hereditary prostate cancer and other genetic predispositions to prostate cancer. Urol Int. 1998;60(Suppl. 2):30-4. https://doi.org/10.1159/000056549

23. Carrion-Salip D, Panosa C, Menendez JA, Puig T, Oliveras G, Pandiella A, et al. Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands. Int J Oncol. 2012;41(3):1128-38. https://doi.org/10.3892/ijo.2012.1509

24. Sidorova EA, Zhernov YV, Antsupova MA, Khadzhieva KR, Izmailova AA, Kraskevich DA, et al. The role of different types of microRNA in the pathogenesis of breast and prostate cancer. Int J Mol Sci. 2023;24(3):1980. https://doi.org/10.3390/ijms24031980

25. Zhang P, Chen L, Zhou F, He Z, Wang G, Luo Y. NRP1 promotes prostate cancer progression via modulating EGFR-dependent AKT pathway activation. Cell Death Dis. 2023;14(2):159. https://doi.org/10.1038/s41419-023-05696-1

26. Höti N, Lih TS, Pan J, Zhou Y, Yang G, Deng A, et al. A comprehensive analysis of FUT8 overexpressing prostate cancer cells reveals the role of EGFR in castration resistance. Cancers. 2020;12(2):468. https://doi.org/10.3390/cancers12020468

27. Traish A, Morgentaler A. Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth. Br J Cancer. 2009;101(12):1949-56. https://doi.org/10.1038/sj.bjc.6605376

28. Inoue J, Inazawa J. Cancer-associated miRNAs and their therapeutic potential. J Hum Genet. 2021;66(9):937-45. https://doi.org/10.1038/s10038-021-00938-6

29. Palanichamy JK, Rao DS. miRNA dysregulation in cancer: towards a mechanistic understanding. Front Genet. 2014;5:54. https://doi.org/10.3389/fgene.2014.00054

30. Hussen BM, Hidayat HJ, Salihi A, Sabir DK, Taheri M, Ghafouri- Fard S. MicroRNA: a signature for cancer progression. Biomed Pharmacother. 2021;138:111528. https://doi.org/10.1016/j.biopha.2021.111528

31. Jiang FN, Liang YX, Wei W, Zou CY, Chen GX, Wan YP, et al. Functional classification of prostate cancer associated miRNAs through CRISPR/Cas9 mediated gene knockout. Mol Med Rep. 2020;22(5):3777-84. https://doi.org/10.3892/mmr.2020.11491

32. Massillo C, Dalton GN, Farré PL, De Luca P, De Siervi A. Implications of microRNA dysregulation in the development of prostate cancer. Reproduction. 2017;154(4):R81-97. https://doi.org/10.1530/REP-17-0322

33. Fang Y, Gao W. Roles of microRNAs during prostatic tumorigenesis and tumor progression. Oncogene. 2014;33(2):135-47. https://doi.org/10.1038/onc.2013.54

34. Wang S, Wang X, Li J, Meng S, Liang Z, Xu X, et al. c-Met, CREB1 and EGFR are involved in miR-493-5p inhibition of EMT via AKT/GSK-3β/Snail signaling in prostate cancer. Oncotarget. 2017;8(47):82303. https://doi.org/10.18632/oncotarget.19398

35. Ferri C, Di Biase A, Bocchetti M, Zappavigna S, Wagner S, Le Vu P, et al. MiR-423-5p prevents MALAT1-mediated proliferation and metastasis in prostate cancer. J Exp Clin Cancer Res. 2022;41(1):1- 16. https://doi.org/10.1186/s13046-021-02233-w

36. Chong ZX, Yeap SK, Ho WY, Fang CM. Unveiling the tumour-regulatory roles of miR-1275 in cancer. Pathol-Res Pract. 2022;230:153745. https://doi.org/10.1016/j.prp.2021.153745

37. Xie C, Wu Y, Fei Z, Fang Y, Xiao S, Su H. MicroRNA-1275 induces radiosensitization in oesophageal cancer by regulating epithelial-to-mesenchymal transition via Wnt/β-catenin pathway. J Cell Mol Med. 2020;24(1):747-59. https://doi.org/10.1111/jcmm.14784

38. Han X, Li M, Xu J, Fu J, Wang X, Wang J, et al. miR-1275 targets MDK/AKT signaling to inhibit breast cancer chemoresistance by lessening the properties of cancer stem cells. Int J Biol Sci. 2023;19(1):89. https://doi.org/10.7150/ijbs.74227

39. Neralla M, Preethi A, Selvakumar S, Sekar D. Expression levels of microRNA-7110 in oral squamous cell carcinoma. Minerva Dent Oral Sci. 2024;73(3):155-60. https://doi.org/10.23736/S2724-6329.23.04801-5

40. Zhao M, Hou Y, Du YE, Yang L, Qin Y, Peng M, et al. Drosha-independent miR-6778-5p strengthens gastric cancer stem cell stemness via regulation of cytosolic one-carbon folate metabolism. Cancer Lett. 2020;478:8-21. https://doi.org/10.1016/j.canlet.2020.02.040

41. Diepenbruck M, Tiede S, Saxena M, Ivanek R, Kalathur RKR, Lüönd F, et al. miR-1199-5p and Zeb1 function in a double-negative feedback loop potentially coordinating EMT and tumour metastasis. Nat Commun. 2017;8(1):1168. https://doi.org/10.1038/s41467-017-01197-w

42. Sato A, Yamamoto A, Shimotsuma A, Ogino Y, Funayama N, Takahashi Y, et al. Intracellular microRNA expression patterns influence cell death fates for both necrosis and apoptosis. FEBS Open Bio. 2020;10(11):2417-26. https://doi.org/10.1002/2211-5463.12995

43. Olivan M, Garcia M, Suárez L, Guiu M, Gros L, Méndez O, et al. Loss of microRNA-135b enhances bone metastasis in prostate cancer and predicts aggressiveness in human prostate samples. Cancers. 2021;13(24):6202. https://doi.org/10.3390/cancers13246202

44. Ru P, Steele R, Newhall P, Phillips NJ, Toth K, Ray RB. miRNA-29b suppresses prostate cancer metastasis by regulating epithelial-mesenchymal transition signaling. Mol Cancer Ther. 2012;11(5):1166-73. https://doi.org/10.1158/1535-7163.MCT-12-0100

45. Ikeda Y, Morikawa S, Nakashima M, Yoshikawa S, Taniguchi K, Sawamura H, et al. CircRNAs and RNA-binding proteins involved in the pathogenesis of cancers or central nervous system disorders. Non-coding RNA. 2023;9(2):23. https://doi.org/10.3390/ncrna9020023

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