Expression of the Low-density Lipoprotein Receptor (LDLR) Gene Family in CD133+/CD44+ Prostate Cancer Stem Cells

Abstract

Aim: The low-density lipoprotein receptor gene (LDLR) family plays a fundamental role in many malignancies and may have a putative cancer-boosting function. In our study, we have attempted to comparatively investigate the differential gene expressions of LDLR family in normal prostate epithelial cell line (RWPE-1), prostate cancer cell line (DU145 cell line), prostate cancer stem cells (DU145 CSCs) and non-CSCs (DU145 non-CSCs, bulk population). Materials and Methods: Cancer stem cells in DU-145 prostate cancer cell line were isolated by flow cytometry according to CD133 and CD44 cell surface properties. Whole transcriptome sequencing data was comprehensively analyzed for each group. The protein-protein interaction network was determined using the STRING protein database. Results: Our data showed that the expression levels of LRP1, LRP3, LRP8 and LRP11 were increased in the DU145 CSCs relative to the normal prostate epithelial cell line. Conclusion: Overall, our data suggest that the LRP functions and/or the expression in prostate cancer may ultimately change the invasive phenotype of the CSCs.

Keywords

• LDLR gen family
• cancer stem cell
• prostate cancer
• transcriptional regulators

References

1. Agliano A, Calvo A, Box C. The challenge of targeting cancer stem cells to halt metastasis. Semin Cancer Biol [Internet]. 2017;44:25–42. Available from: http://dx.doi.org/10.1016/j.semcancer.2017.03.003
2. Gilardoni MB, Ceschin DG, Sahores MM, Oviedo M, Gehrau RC, Chiabrando GA. Decreased expression of the low-density lipoprotein receptor-related protein-1 (LRP-1) in rats with prostate cancer. J Histochem Cytochem Off J Histochem Soc. 2003 Dec;51(12):1575–80.
3. Campion O, Al Khalifa T, Langlois B, Thevenard-Devy J, Salesse S, Savary K, et al. Contribution of the Low-Density Lipoprotein Receptor Family to Breast Cancer Progression. Front Oncol [Internet]. 2020;10. Available from: https://www.frontiersin.org/article/10.3389/fonc.2020.00882
4. May P, Woldt E, Matz RL, Boucher P. The LDL receptor-related protein (LRP) family: an old family of proteins with new physiological functions. Ann Med. 2007;39(3):219–28.
5. Jeong Y-H, Sekiya M, Hirata M, Ye M, Yamagishi A, Lee S-M, et al. The low-density lipoprotein receptor-related protein 10 is a negative regulator of the canonical Wnt/beta-catenin signaling pathway. Biochem Biophys Res Commun. 2010 Feb;392(4):495–9.
6. Peck B, Schulze A. Lipid Metabolism at the Nexus of Diet and Tumor Microenvironment. Trends in Cancer [Internet]. 2019;5(11):693–703. Available from: https://www.sciencedirect.com/science/article/pii/S2405803319301906
7. Furuya Y, Sekine Y, Kato H, Miyazawa Y, Koike H, Suzuki K. Low-density lipoprotein receptors play an important role in the inhibition of prostate cancer cell proliferation by statins. Prostate Int. 2016 Jun;4(2):56–60.
8. Tirinato L, Liberale C, Di Franco S, Candeloro P, Benfante A, La Rocca R, et al. Lipid droplets: a new player in colorectal cancer stem cells unveiled by spectroscopic imaging. Stem Cells. 2015 Jan;33(1):35–44.

9. Yasumoto Y, Miyazaki H, Vaidyan LK, Kagawa Y, Ebrahimi M, Yamamoto Y, et al. Inhibition of Fatty Acid Synthase Decreases Expression of Stemness Markers in Glioma Stem Cells. PLoS One. 2016;11(1):e0147717.
10. Li J, Condello S, Thomes-Pepin J, Ma X, Xia Y, Hurley TD, et al. Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells. Cell Stem Cell. 2017 Mar;20(3):303-314.e5.
11. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019 Jan;47(D1):D607–13.
12. Binal Z, Açıkgöz E, Kızılay F, Öktem G, Altay B. Cross-talk between ribosome biogenesis, translation, and mTOR in CD133+ 4/CD44+ prostate cancer stem cells. Clin Transl Oncol [Internet]. 2020;22(7):1040–8. Available from: https://doi.org/10.1007/s12094-019-02229-1
13. Soner BC, Aktug H, Acikgoz E, Duzagac F, Guven U, Ayla S, et al. Induced growth inhibition, cell cycle arrest and apoptosis in CD133+/CD44+prostate cancer stem cells by flavopiridol. Int J Mol Med. 2014;34(5):1249–56.
14. Acikgoz E, Guven U, Duzagac F, Uslu R, Kara M, Soner BC, et al. Enhanced G2/M arrest, caspase related apoptosis and reduced E-cadherin dependent intercellular adhesion by trabectedin in prostate cancer stem cells. PLoS One. 2015;10(10):1–17.
15. Li Y, Lu W, Marzolo MP, Bu G. Differential functions of members of the low density lipoprotein receptor family suggested by their distinct endocytosis rates. J Biol Chem. 2001 May;276(21):18000–6.
16. Dun B, Sharma A, Teng Y, Liu H, Purohit S, Xu H, et al. Mycophenolic acid inhibits migration and invasion of gastric cancer cells via multiple molecular pathways. PLoS One. 2013;8(11):e81702.
17. Le Cigne A, Chièze L, Beaussart A, El-Kirat-Chatel S, Dufrêne YF, Dedieu S, et al. Analysis of the effect of LRP-1 silencing on the invasive potential of cancer cells by nanomechanical probing and adhesion force measurements using atomic force microscopy. Nanoscale [Internet]. 2016;8(13):7144–54. Available from: http://dx.doi.org/10.1039/C5NR08649C
18. Van Gool B, Dedieu S, Emonard H, Roebroek AJM. The Matricellular Receptor LRP1 Forms an Interface for Signaling and Endocytosis in Modulation of the Extracellular Tumor Environment. Front Pharmacol. 2015;6:271.
19. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10(8):789–99.
20. Holt SK, Karyadi DM, Kwon EM, Stanford JL, Nelson PS, Ostrander EA. Association of megalin genetic polymorphisms with prostate cancer risk and prognosis. Clin Cancer Res. 2008;14(12):3823–31.
21. Annabi B, Doumit J, Plouffe K, Laflamme C, Lord-Dufour S, Béliveau R. Members of the low-density lipoprotein receptor-related proteins provide a differential molecular signature between parental and CD133(+) DAOY medulloblastoma cells. Mol Carcinog. 2010;49(7):710–7.
22. Emami Nejad A, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M, et al. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int [Internet]. 2021;21(1):62. Available from: https://doi.org/10.1186/s12935-020-01719-5
23. Ishii H, Kim DH, Fujita T, Endo Y, Saeki S, Yamamoto TT. cDNA cloning of a new low-density lipoprotein receptor-related protein and mapping of its gene (LRP3) to chromosome bands 19q12-q13. 2. Genomics. 1998 Jul;51(1):132–5.
24. Chin EN, Martin JA, Kim S, Fakhraldeen SA, Alexander CM. Lrp5 Has a Wnt-Independent Role in Glucose Uptake and Growth for Mammary Epithelial Cells. Mol Cell Biol. 2015 Dec;36(6):871–85.
25. Tomita Y, Kim DH, Magoori K, Fujino T, Yamamoto TT. A novel low-density lipoprotein receptor-related protein with type II membrane protein-like structure is abundant in heart. J Biochem. 1998 Oct;124(4):784–9.
26. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature [Internet]. 2005;434(7035):843–50. Available from: https://doi.org/10.1038/nature03319
27. Kafka A, Bašić-Kinda S, Pećina-Šlaus N. The cellular story of dishevelleds. Croat Med J. 2014 Oct 30;55:459–67.
28. Ma J, Lu W, Chen D, Xu B, Li Y. Role of Wnt Co-Receptor LRP6 in Triple Negative Breast Cancer Cell Migration and Invasion. J Cell Biochem. 2017 Sep;118(9):2968–76.
29. Annese T, Tamma R, De Giorgis M, Ribatti D. microRNAs Biogenesis, Functions and Role in Tumor Angiogenesis. Front Oncol [Internet]. 2020;10. Available from: https://www.frontiersin.org/article/10.3389/fonc.2020.581007
30. Pencheva N, Tran H, Buss C, Huh D, Drobnjak M, Busam K, et al. Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis. Cell. 2012 Nov;151(5):1068–82.
31. Fang Z, Zhong M, Zhou L, Le Y, Wang H, Fang Z. Low-density lipoprotein receptor-related protein 8 facilitates the proliferation and invasion of non-small cell lung cancer cells by regulating the Wnt/β-catenin signaling pathway. Bioengineered [Internet]. 2022 Mar 1;13(3):6807–18. Available from: https://doi.org/10.1080/21655979.2022.2036917
32. Gan S, Ye J, Li J, Hu C, Wang J, Xu D, et al. LRP11 activates β-catenin to induce PD-L1 expression in prostate cancer. J Drug Target. 2020 Jun;28(5):508–15.