Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

RhoBTB3 Regulates Proliferation and Invasion of Breast Cancer Cells via Col1a1

  • Kim, Kyungho (Targeted Therapy Branch, Division of Rare and Refractory Cancer, Research Institute, National Cancer Center) ;
  • Kim, Youn-Jae (Targeted Therapy Branch, Division of Rare and Refractory Cancer, Research Institute, National Cancer Center)
  • Received : 2021.12.01
  • Accepted : 2022.05.09
  • Published : 2022.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Breast cancer is the leading cause of cancer-related death in women worldwide, despite medical and technological advancements. The RhoBTB family consists of three isoforms: RhoBTB1, RhoBTB2, and RhoBTB3. RhoBTB1 and RhoBTB2 have been proposed as tumor suppressors in breast cancer. However, the roles of RhoBTB3 proteins are unknown in breast cancer. Bioinformatics analysis, including Oncomine, cBioportal, was used to evaluate the potential functions and prognostic values of RhoBTB3 and Col1a1 in breast cancer. qRT-PCR analysis and immunoblotting assay were performed to investigate relevant expression. Functional experiments including proliferation assay, invasion assay, and flow cytometry assay were conducted to determine the role of RhoBTB3 and Col1a1 in breast cancer cells. RhoBTB3 mRNA levels were significantly up-regulated in breast cancer tissues as compared to in adjacent normal tissues. Moreover, RhoBTB3 expression was found to be associated with Col1a1 expression. Decreasing RhoBTB3 expression may lead to decreases in the proliferative and invasive properties of breast cancer cells. Further, Col1a1 knockdown in breast cancer cells limited the proliferative and invasive ability of cancer cells. Knockdown of RhoBTB3 may exert inhibit the proliferation, migration, and metastasis of breast cancer cells by repressing the expression of Col1a1, providing a novel therapeutic strategy for treating breast cancer.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2018R1A6A3A01012525, 2019R1A2C1086258, and 2020R1C1C1012977), and by the National Cancer Center grant (NCC-2010250 and NCC-2210750).

References

  1. Akkari, Y.M., Bateman, R.L., Reifsteck, C.A., Olson, S.B., and Grompe, M. (2000). DNA replication is required to elicit cellular responses to psoralen- induced DNA interstrand cross-links. Mol. Cell. Biol. 20, 8283-8289. https://doi.org/10.1128/MCB.20.21.8283-8289.2000
  2. Anastasiadi, Z., Lianos, G.D., Ignatiadou, E., Harissis, H.V., and Mitsis, M. (2017). Breast cancer in young women: an overview. Updates Surg. 69, 313-317. https://doi.org/10.1007/s13304-017-0424-1
  3. Aspenstrom, P., Fransson, A., and Saras, J. (2004). Rho GTPases have diverse effects on the organization of the actin filament system. Biochem. J. 377, 327-337. https://doi.org/10.1042/bj20031041
  4. Aspenstrom, P., Ruusala, A., and Pacholsky, D. (2007). Taking Rho GTPases to the next level: the cellular functions of atypical Rho GTPases. Exp. Cell Res. 313, 3673-3679. https://doi.org/10.1016/j.yexcr.2007.07.022
  5. Berthold, J., Schenkova, K., Ramos, S., Miura, Y., Furukawa, M., Aspenstrom, P., and Rivero, F. (2008a). Characterization of RhoBTB-dependent Cul3 ubiquitin ligase complexes--evidence for an autoregulatory mechanism. Exp. Cell Res. 314, 3453-3465. https://doi.org/10.1016/j.yexcr.2008.09.005
  6. Berthold, J., Schenkova, K., and Rivero, F. (2008b). Rho GTPases of the RhoBTB subfamily and tumorigenesis. Acta Pharmacol. Sin. 29, 285-295. https://doi.org/10.1111/j.1745-7254.2008.00773.x
  7. Boudhraa, Z., Carmona, E., Provencher, D., and Mes-Masson, A.M. (2020). Ran GTPase: a key player in tumor progression and metastasis. Front. Cell Dev. Biol. 8, 345.
  8. Burns-Cox, N., Avery, N.C., Gingell, J.C., and Bailey, A.J. (2001). Changes in collagen metabolism in prostate cancer: a host response that may alter progression. J. Urol. 166, 1698-1701. https://doi.org/10.1016/S0022-5347(05)65656-X
  9. Burrows, J.F., Kelvin, A.A., McFarlane, C., Burden, R.E., McGrattan, M.J., De la Vega, M., Govender, U., Quinn, D.J., Dib, K., Gadina, M., et al. (2009). USP17 regulates Ras activation and cell proliferation by blocking RCE1 activity. J. Biol. Chem. 284, 9587-9595. https://doi.org/10.1074/jbc.M807216200
  10. Cancer Genome Atlas Network (2012). Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70. https://doi.org/10.1038/nature11412
  11. Cao, H., Thompson, H., Krueger, E., and McNiven, M. (2000). Disruption of Golgi structure and function in mammalian cells expressing a mutant dynamin. J. Cell Sci. 113, 1993-2002. https://doi.org/10.1242/jcs.113.11.1993
  12. Chen, D., Chen, G., Jiang, W., Fu, M., Liu, W., Sui, J., Xu, S., Liu, Z., Zheng, X., Chi, L., et al. (2019). Association of the collagen signature in the tumor microenvironment with lymph node metastasis in early gastric cancer. JAMA Surg. 154, e185249.
  13. Choi, Y.M., Kim, K.B., Lee, J.H., Chun, Y.K., An, I.S., An, S., and Bae, S. (2017). DBC2/RhoBTB2 functions as a tumor suppressor protein via Musashi-2 ubiquitination in breast cancer. Oncogene 36, 2802-2812. https://doi.org/10.1038/onc.2016.441
  14. Colanzi, A., Carcedo, C.H., Persico, A., Cericola, C., Turacchio, G., Bonazzi, M., Luini, A., and Corda, D. (2007). The Golgi mitotic checkpoint is controlled by BARS-dependent fission of the Golgi ribbon into separate stacks in G2. EMBO J. 26, 2465-2476. https://doi.org/10.1038/sj.emboj.7601686
  15. Desreux, J.A.C. (2018). Breast cancer screening in young women. Eur. J. Obstet. Gynecol. Reprod. Biol. 230, 208-211. https://doi.org/10.1016/j.ejogrb.2018.05.018
  16. Dudley, D.T., Li, X.Y., Hu, C.Y., Kleer, C.G., Willis, A.L., and Weiss, S.J. (2014). A 3D matrix platform for the rapid generation of therapeutic anti-human carcinoma monoclonal antibodies. Proc. Natl. Acad. Sci. U. S. A. 111, 14882-14887. https://doi.org/10.1073/pnas.1410996111
  17. Espinosa, E.J., Calero, M., Sridevi, K., and Pfeffer, S.R. (2009). RhoBTB3: a Rho GTPase-family ATPase required for endosome to Golgi transport. Cell 137, 938-948. https://doi.org/10.1016/j.cell.2009.03.043
  18. Fang, S., Dai, Y., Mei, Y., Yang, M., Hu, L., Yang, H., Guan, X., and Li, J. (2019). Clinical significance and biological role of cancer-derived Type I collagen in lung and esophageal cancers. Thorac. Cancer 10, 277-288. https://doi.org/10.1111/1759-7714.12947
  19. Gurel, P.S., Hatch, A.L., and Higgs, H.N. (2014). Connecting the cytoskeleton to the endoplasmic reticulum and Golgi. Curr. Biol. 24, R660-R672. https://doi.org/10.1016/j.cub.2014.05.033
  20. Harbeck, N. and Gnant, M. (2017). Breast cancer. Lancet 389, 1134-1150. https://doi.org/10.1016/S0140-6736(16)31891-8
  21. Jafari, S.H., Saadatpour, Z., Salmaninejad, A., Momeni, F., Mokhtari, M., Nahand, J.S., Rahmati, M., Mirzaei, H., and Kianmehr, M. (2018). Breast cancer diagnosis: imaging techniques and biochemical markers. J. Cell. Physiol. 233, 5200-5213. https://doi.org/10.1002/jcp.26379
  22. Ji, W. and Rivero, F. (2016). Atypical Rho GTPases of the RhoBTB subfamily: roles in vesicle trafficking and tumorigenesis. Cells 5, 28.
  23. Junaid, M., Muhseen, Z.T., Ullah, A., Wadood, A., Liu, J., and Zhang, H. (2014). Molecular modeling and molecular dynamics simulation study of the human Rab9 and RhoBTB3 C-terminus complex. Bioinformation 10, 757-763. https://doi.org/10.6026/97320630010757
  24. Koh, E.Y., You, J.E., Jung, S.H., and Kim, P.H. (2020). Biological functions and identification of novel biomarker expressed on the surface of breast cancer-derived cancer stem cells via proteomic analysis. Mol. Cells 43, 384-396.
  25. Laurent, G. (1987). Dynamic state of collagen: pathways of collagen degradation in vivo and their possible role in regulation of collagen mass. Am. J. Physiol. 252 (1 Pt 1), C1-C9. https://doi.org/10.1152/ajpcell.1987.252.1.C1
  26. Li, J., Ding, Y., and Li, A. (2016). Identification of COL1A1 and COL1A2 as candidate prognostic factors in gastric cancer. World J Surg Oncol 14, 297.
  27. Liu, J., Shen, J.X., Wu, H.T., Li, X.L., Wen, X.F., Du, C.W., and Zhang, G.J. (2018). Collagen 1A1 (COL1A1) promotes metastasis of breast cancer and is a potential therapeutic target. Discov. Med. 25, 211-223.
  28. Liu, T., Ye, P., Ye, Y., Lu, S., and Han, B. (2020). Circular RNA hsa_circRNA_002178 silencing retards breast cancer progression via microRNA-328-3p-mediated inhibition of COL1A1. J. Cell. Mol. Med. 24, 2189-2201. https://doi.org/10.1111/jcmm.14875
  29. Lu, A. and Pfeffer, S.R. (2013). Golgi-associated RhoBTB3 targets cyclin E for ubiquitylation and promotes cell cycle progression. J. Cell Biol. 203, 233-250. https://doi.org/10.1083/jcb.201305158
  30. Ma, H.P., Chang, H.L., Bamodu, O.A., Yadav, V.K., Huang, T.Y., Wu, A.T.H., Yeh, C.T., Tsai, S.H., and Lee, W.H. (2019). Collagen 1A1 (COL1A1) is a reliable biomarker and putative therapeutic target for hepatocellular carcinogenesis and metastasis. Cancers (Basel) 11, 786.
  31. Machamer, C.E. (2015). The Golgi complex in stress and death. Front. Neurosci. 9, 421.
  32. Manolaridis, I., Kulkarni, K., Dodd, R.B., Ogasawara, S., Zhang, Z., Bineva, G., Reilly, N.O., Hanrahan, S.J., Thompson, A.J., Cronin, N., et al. (2013). Mechanism of farnesylated CAAX protein processing by the intramembrane protease Rce1. Nature 504, 301-305. https://doi.org/10.1038/nature12754
  33. Martins Cavaco, A.C., Damaso, S., Casimiro, S., and Costa, L. (2020). Collagen biology making inroads into prognosis and treatment of cancer progression and metastasis. Cancer Metastasis Rev. 39, 603-623. https://doi.org/10.1007/s10555-020-09888-5
  34. McKinnon, C.M. and Mellor, H. (2017). The tumor suppressor RhoBTB1 controls Golgi integrity and breast cancer cell invasion through METTL7B. BMC Cancer 17, 145.
  35. Mysior, M.M. and Simpson, J.C. (2021). Emerging roles for Rho GTPases operating at the Golgi complex. Small GTPases 12, 311-322. https://doi.org/10.1080/21541248.2020.1812873
  36. Nguyen, T.H., Ralbovska, A., and Kugler, J.M. (2020). RhoBTB proteins regulate the Hippo pathway by antagonizing ubiquitination of LKB1. G3 (Bethesda) 10, 1319-1325. https://doi.org/10.1534/g3.120.401038
  37. Nissen, N.I., Karsdal, M., and Willumsen, N. (2019). Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology. J. Exp. Clin. Cancer Res. 38, 115.
  38. Odle, T.G. (2017). Precision medicine in breast cancer. Radiol. Technol. 88, 401M-421M.
  39. Pucci-Minafra, I., Albanese, N.N., Di Cara, G., Minafra, L., Marabeti, M.R., and Cancemi, P. (2008). Breast cancer cells exhibit selective modulation induced by different collagen substrates. Connect. Tissue Res. 49, 252-256. https://doi.org/10.1080/03008200802147779
  40. Reichheld, J.P., Vernoux, T., Lardon, F., Van Montagu, M., and Inze, D. (1999). Specific checkpoints regulate plant cell cycle progression in response to oxidative stress. Plant J. 17, 647-656. https://doi.org/10.1046/j.1365-313X.1999.00413.x
  41. Shi, Y., Duan, Z., Zhang, X., Zhang, X., Wang, G., and Li, F. (2019). Down-regulation of the let-7i facilitates gastric cancer invasion and metastasis by targeting COL1A1. Protein Cell 10, 143-148. https://doi.org/10.1007/s13238-018-0550-7
  42. Siwik, D.A., Pagano, P.J., and Colucci, W.S. (2001). Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am. J. Physiol. Cell Physiol. 280, C53-C60. https://doi.org/10.1152/ajpcell.2001.280.1.C53
  43. Slocum, E. and Germain, D. (2019). Collagen and PAPP-A in the etiology of postpartum breast cancer. Horm. Cancer 10, 137-144. https://doi.org/10.1007/s12672-019-00368-z
  44. St-Pierre, B., Jiang, Z., Egan, S.E., and Zacksenhaus, E. (2004). High expression during neurogenesis but not mammogenesis of a murine homologue of the Deleted in Breast Cancer2/Rhobtb2 tumor suppressor. Gene Expr. Patterns 5, 245-251. https://doi.org/10.1016/j.modgep.2004.07.009
  45. Taniguchi, M. and Yoshida, H. (2017). TFE3, HSP47, and CREB3 pathways of the mammalian Golgi stress response. Cell Struct. Funct. 42, 27-36. https://doi.org/10.1247/csf.16023
  46. Waks, A.G. and Winer, E.P. (2019). Breast cancer treatment: a review. JAMA 321, 288-300. https://doi.org/10.1001/jama.2018.19323
  47. Woldu, S.L., Hutchinson, R.C., Krabbe, L.M., Sanli, O., and Margulis, V. (2018). The Rho GTPase signalling pathway in urothelial carcinoma. Nat. Rev. Urol. 15, 83-91. https://doi.org/10.1038/nrurol.2017.184
  48. Wolf, K., Alexander, S., Schacht, V., Coussens, L.M., von Andrian, U.H., van Rheenen, J., Deryugina, E., and Friedl, P. (2009). Collagen-based cell migration models in vitro and in vivo. Semin. Cell Dev. Biol. 20, 931-941. https://doi.org/10.1016/j.semcdb.2009.08.005
  49. Xu, S., Xu, H., Wang, W., Li, S., Li, H., Li, T., Zhang, W., Yu, X., and Liu, L. (2019). The role of collagen in cancer: from bench to bedside. J. Transl. Med. 17, 309.
  50. Zhang, C.S., Liu, Q., Li, M., Lin, S.Y., Peng, Y., Wu, D., Li, T.Y., Fu, Q., Jia, W., Wang, X., et al. (2015). RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect. Cell Res. 25, 1025-1042. https://doi.org/10.1038/cr.2015.90
  51. Zhang, Z., Wang, Y., Zhang, J., Zhong, J., and Yang, R. (2018). COL1A1 promotes metastasis in colorectal cancer by regulating the WNT/PCP pathway. Mol. Med. Rep. 17, 5037-5042.
  52. Zhu, J., Xiong, G., Fu, H., Evers, B.M., Zhou, B.P., and Xu, R. (2015). Chaperone Hsp47 drives malignant growth and invasion by modulating an ECM gene network. Cancer Res. 75, 1580-1591.