Androgen Receptor Promotes Lung Cancer Metastasis by Modifying the miR23a-3p/EPHB2 Pathway

Abstract

Objective

This study aimed to investigate the reasons behind the lower survival rates in male lung cancer patients than in female lung cancer patients.

Methods

Through various techniques, such as Argonaute immunoprecipitation, luciferase assays, and ChIP, this study confirmed the positive effects of androgen receptor (AR) on lung cancer cell invasion across different in vitro cell lines and in vivo mouse models.

Results

The findings suggest that AR enhanced the invasion of lung cancer cells by modifying EPHB2 signals at the protein expression level, which in turn required changes in miRNA-23a-3p. Restoring miRNA-23a-3p could counteract the intensified invasion of lung cancer cells mediated by AR.

Conclusion

This study revealed that AR may facilitate the lung cancer matastasis by modulating miRNA-23a-3p/EPHB2 signaling and that targeting this signaling pathway could provide new approaches to inhibit lung cancer metastasis.

References

[1] SiegelRL, MillerKD, WagleNS, et al. . Cancer statistics, 2023. CA Cancer J Clin, 2023, 3(1): 17-48

[2] LiuS, HuC, LiM, et al. . Androgen receptor suppresses lung cancer invasion and increases cisplatin response via decreasing TPD52 expression. Int J Biol Sci, 2023, 19(12): 3709-3725

[3] AsavasupreecharT, ChanMSM, SaitoR, et al. . Sex steroid metabolism and actions in non-small cell lung carcinoma. J Steroid Biochem Mol Biol, 2019, 193: 105440

[4] SiegfriedJM. Smoking out reproductive hormone actions in lung cancer. Mol Cancer Res MCR, 2014, 12(1): 24-31

[5] LiuW, YuC, LiJ, et al. . The Roles of EphB2 in Cancer. Front Cell Dev Biol, 2022, 10: 788587

[6] YuanL, YiW, SunC, et al. . EphB2 activates CREB-dependent expression of Annexin A1 to regulate dendritic spine morphogenesis. Biochem Biophys Res Commun, 2021, 20(584): 107-115

[7] DienerC, KellerA, MeeseE. Emerging concepts of miRNA therapeutics: from cells to clinic. Trends Genet TIG, 2022, 38(6): 613-626

[8] NiuY, ChangTM, YehS, et al. . Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails. Oncogene, 2010, 29(25): 3593-604

[9] GangwarSK, KumarA, YapKC, et al. . Targeting Nuclear Receptors in Lung Cancer-Novel Therapeutic Prospects. Pharmaceuticals (Basel), 2022, 15(5): 624

[10] ChangC, LeeSO, YehS, et al. . Androgen receptor (AR) differential roles in hormone-related tumors, including prostate, bladder, kidney, lung, breast, and liver. Oncogene, 2014, 33(25): 3225-3234

[11] QuigleyDA, DangHX, ZhaoSG, et al. . Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. Cell, 2018, 174(3): 758-769

[12] GuY, TangYY, WanJX, et al. . Sex difference in the expression of PD- 1 of non-small cell lung cancer. Front Immunol, 2022, 20(13): 1026214

[13] MarwitzS, DepnerS, DvornikovD, et al. . Downregulation of the TG-β Pseudoreceptor BAMBI in Non-Small Cell Lung Cancer Enhances TGF-βSignaling and Invasion. Cancer Res, 2016, 76(13): 3785-3801

[14] XuLJ, WangYC, LanHW, et al. . Grb2-associated binder-2 gene promotes migration of non-small cell lung cancer cells via Akt signaling pathway. Am J Transl Res, 2016, 8(2): 1208-1217

[15] YuanX, WuH, XuHX, et al. . Meta-analysis reveals the correlation of Notch signaling with non-small cell lung cancer progression and prognosis. Sci Rep, 2015, 21(5): 10338

[16] YangH, ZhanL, YangT, et al. . Prevents TGF-beta-induced EMT and cell invasion by repressing SMAD-dependent signaling in non-small cell lung cancer. Oncol Rep, 2021, 45(2): 787-788

[17] LiW, SunM, ZangC, et al. . Upregulated long non-coding RNA AGAP2-AS1 represses LATS2 and KLF2 expression through interacting with EZH2 and LSD1 in non-small-cell lung cancer cells. Cell Death Dis, 2016, 7(5): e2225

[18] GaoQ, LiuW, CaiJ, et al. . EphB2 promotes cervical cancer progression by inducing epithelial-mesenchymal transition. Hum Pathol, 2014, 45(2): 372-381

[19] HoiWL, CarmenONL, EuniceYL, et al. . EPHB2 Activates β-Catenin to Enhance Cancer Stem Cell Properties and Drive Sorafenib Resistance in Hepatocellular Carcinoma. Cancer Res, 2021, 81(12): 3229-3240

[20] YavropoulouMP, AnastasilakisAD, MakrasP, et al. . Serum Profile of microRNAs Linked to Bone Metabolism During Sequential Treatment for Postmenopausal Osteoporosis. J Clin Endocrinol Metab, 2020, 105(8): dgaa368

[21] WangHY, PeiZ, LeeKC, et al. . Simufilam suppresses overactive mTOR and restores its sensitivity to insulin in Alzheimer's disease patient lymphocytes. Front Aging, 2023, 29(4): 1175601

[22] AlbaqamiFF, Abdel-RahmanRF, AlthurwiHN, et al. . Targeting inflammation and oxidative stress for protection against ischemic brain injury in rats using cupressuflavone. Saudi Pharm J, 2024, 32(1): 101933

[23] AsavasupreecharT, ChanMSM, SaitoR, et al. . Sex steroid metabolism and actions in non-small cell lung carcinoma. J Steroid Biochem Mol Biol, 2019, 193: 105440

[24] GiovannelliP, RamarajP, WilliamsC. Editorial: Role of Sex Steroids and Their Receptor in Cancers. Front Endocrinol, 2022, 6(13): 883229