Abstract
Objective
Prostate cancer (PCa) is an aggressive tumor. SHC SH2-domain-binding protein 1 (SHCBP1) has been identified frequently upregulated in various cancers, in addition to PCa. The aims of this study were to determine the relationships between SHCBP1 and clinicopathological characteristics of PCa and to explore the role of SHCBP1 in PCa proliferation and progression.
Methods
Tissue microarray and immunohistochemistry were used to determine the prognostic significance of SHCBP1. The relationship between clinicopathological characteristics of PCa and SHCBP1 was then analyzed using Cox regression analyses. To investigate SHCBP1 functions in vitro and in vivo, we knocked down SHCBP1 in PCa cell lines and established xenograft mice models. A series of cytological function assays were utilized to determine the role of SHCBP1 in cell proliferation, migration, invasion, and apoptosis.
Results
SHCBP1 was significantly upregulated in PCa tissues compared with BPH tissues. Patients with a higher expression of SHCBP1 were associated with poor survival outcomes than those with a lower expression of SHCBP1. Lentivirus-mediated shRNA knockdown of SHCBP1 in prostate cancer cell lines diminished cell growth, migration, and invasion dramatically both in vitro and in vivo, accompanied by an enhanced expression of large tumor suppressor 1 (LATS1) and tumor protein P53 (TP53) and inhibition of MDM2 proto-oncogene (MDM2), which suggested that SHCBP1 may promote proliferation and invasion in vitro via the LATS1–MDM2–TP53 pathway. The results of cycloheximide (CHX) and MG-132 assays indicated that SHCBP1 knockdown could attenuate the degradation of TP53 by the proteasome, prolong the half-life of TP53, and enhance the stabilization of TP53.
Conclusion
These findings suggest that SHCBP1 overexpression contributes to PCa progression and that targeting SHCBP1 might be therapeutically beneficial to patients with PCa.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data generated or analyzed during this study are included in this article.
References
Asano E et al (2013) The Aurora-B-mediated phosphorylation of SHCBP1 regulates cytokinetic furrow ingression. J Cell Sci 126:3263–3270. https://doi.org/10.1242/jcs.124875
Brunner C et al (2017) Alcohol consumption and prostate cancer incidence and progression: a Mendelian randomisation study. Int J Cancer 140:75–85. https://doi.org/10.1002/ijc.30436
Colak D et al (2013) Age-specific gene expression signatures for breast tumors and cross-species conserved potential cancer progression markers in young women. PloS one 8:e63204. https://doi.org/10.1371/journal.pone.0063204
Dong YD, Yuan YL, Yu HB, Tian GJ, Li DY (2018) SHCBP1 is a novel target and exhibits tumorpromoting effects in gastric cancer. Oncol Rep. https://doi.org/10.3892/or.2018.6952
Dong YD, Yuan YL, Yu HB, Tian GJ, Li DY (2019) SHCBP1 is a novel target and exhibits tumorpromoting effects in gastric cancer. Oncol Rep 41:1649–1657. https://doi.org/10.3892/or.2018.6952
Epstein JI et al (2016) A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol 69:428–435. https://doi.org/10.1016/j.eururo.2015.06.046
Feng W et al (2016) SHCBP1 is over-expressed in breast cancer and is important in the proliferation and apoptosis of the human malignant breast cancer cell line. Gene 587:91–97. https://doi.org/10.1016/j.gene.2016.04.046
Han CK et al (2015) Comparison of Immunomodulatory and Anticancer Activities in Different Strains of Tremella fuciformis Berk. Am J Chin Med 43:1637–1655. https://doi.org/10.1142/s0192415x15500937
Hirata H et al (2011) DICKKOPF-4 activates the noncanonical c-Jun-NH2 kinase signaling pathway while inhibiting the Wnt-canonical pathway in human renal cell carcinoma. Cancer 117:1649–1660. https://doi.org/10.1002/cncr.25666
Hoffman RM et al (2017) Treatment decision regret among long-term survivors of localized prostate cancer: results from the prostate cancer outcomes study. J Clin Oncol: Off J Am Soc Clin Oncol 35:2306–2314. https://doi.org/10.1200/jco.2016.70.6317
Lee SJ, Kim WJ, Moon SK (2012) Role of the p38 MAPK signaling pathway in mediating interleukin-28A-induced migration of UMUC-3 cells. Int J Mol Med 30:945–952. https://doi.org/10.3892/ijmm.2012.1064
Li J et al (2016) Integration of lipidomics and transcriptomics unravels aberrant lipid metabolism and defines cholesteryl oleate as potential biomarker of prostate cancer. Sci Rep 6:20984. https://doi.org/10.1038/srep20984
Lin TT et al (2019) Risk factors for progression to castration-resistant prostate cancer in metastatic prostate cancer patients. J Cancer 10:5608–5613. https://doi.org/10.7150/jca.30731
Liu L et al (2019) EGF-induced nuclear localization of SHCBP1 activates beta-catenin signaling and promotes cancer progression. Oncogene 38:747–764. https://doi.org/10.1038/s41388-018-0473-z
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−∆∆C(T)) method. Methods (San Diego, Calif) 25:402–408. https://doi.org/10.1006/meth.2001.1262
Malik SA, Khan MS, Dar M, Hussain MU, Shah MA, Shafi SM, Mudassar S (2018) Molecular alterations and expression dynamics of LATS1 and LATS2 genes in non-small-cell lung carcinoma. Pathol Oncol Res 24:207–214. https://doi.org/10.1007/s12253-017-0225-3
Mandel P et al (2016) Salvage radical prostatectomy for recurrent prostate cancer: verification of european association of urology guideline criteria. BJU Int 117:55–61. https://doi.org/10.1111/bju.13103
Matallanas D et al (2011) Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. Mol Cell 44:893–906. https://doi.org/10.1016/j.molcel.2011.10.016
Naselli A, Introini C, Andreatta R, Spina B, Truini M, Puppo P (2009) Prognostic factors of persistently detectable PSA after radical prostatectomy. Int J Urol: Off J Japn Urol Assoc 16:82–86. https://doi.org/10.1111/j.1442-2042.2008.02198.x
Ornitz DM, Itoh N (2015) The fibroblast growth factor signaling pathway Wiley interdisciplinary reviews. Dev Biol 4:215–266. https://doi.org/10.1002/wdev.176
Peng C, Guo W, Yang Y, Zhao H (2008) Downregulation of SS18-SSX1 expression by small interfering RNA inhibits growth and induces apoptosis in human synovial sarcoma cell line HS-SY-II in vitro. Eur J Cancer Prev: Off J Eur Cancer Prev Org (ECP) 17:392–398. https://doi.org/10.1097/cej.0b013e328305a11b
Piccaluga PP et al (2007) Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. J Clin Invest 117:823–834. https://doi.org/10.1172/jci26833
Ploussard G et al (2013) Predictive factors of oncologic outcomes in patients who do not achieve undetectable prostate specific antigen after radical prostatectomy. J Urol 190:1750–1756. https://doi.org/10.1016/j.juro.2013.04.073
Qiao J et al (2015) Filamin C a dysregulated protein in cancer revealed by label-free quantitative proteomic analyses of human gastric cancer cells. Oncotarget 6:1171–1189. https://doi.org/10.18632/oncotarget.2645
Raatikainen S, Aaaltomaa S, Karja V, Soini Y (2015) Increased peroxiredoxin 6 expression predicts biochemical recurrence in prostate cancer patients after radical prostatectomy. Anticancer Res 35:6465–6470
Reis ST et al (2012) Underexpression of MMP-2 and its regulators, TIMP2, MT1-MMP and IL-8, is associated with prostate cancer. Int Braz J Urol: Off J Braz Soc Urol 38:167–174
Saafan H et al (2016) Utilising the EGFR interactome to identify mechanisms of drug resistance in non-small cell lung cancer—proof of concept towards a systems pharmacology approach. Eur J Pharm Sci: Off J Eur Fed Pharm Sci 94:20–32. https://doi.org/10.1016/j.ejps.2016.04.025
Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. Cancer J Clin 65:5–29. https://doi.org/10.3322/caac.21254
Tao HC, Wang HX, Dai M, Gu CY, Wang Q, Han ZG, Cai B (2013) Targeting SHCBP1 inhibits cell proliferation in human hepatocellular carcinoma cells. Asian Pac J Cancer Prev 14:5645–5650. https://doi.org/10.7314/apjcp.2013.14.10.5645
Teufel A, Marquardt JU, Galle PR (2012) Novel insights in the genetics of HCC recurrence and advances in transcriptomic data integration. J Hepatol 56:279–281. https://doi.org/10.1016/j.jhep.2011.05.035
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. Cancer J Clin 65:87–108. https://doi.org/10.3322/caac.21262
Truffinet V, Pinaud E, Cogne N, Petit B, Guglielmi L, Cogne M, Denizot Y (2007) The 3′ IgH locus control region is sufficient to deregulate a c-myc transgene and promote mature B cell malignancies with a predominant Burkitt-like phenotype. J Immunol (Baltimore, Md: 1950) 179:6033–6042
Wu YP et al (2016) Comparison of the efficacy and feasibility of en bloc transurethral resection of bladder tumor versus conventional transurethral resection of bladder tumor: a meta-analysis. Medicine 95:e5372. https://doi.org/10.1097/md.0000000000005372
Wu D, Yang X, Peng H, Guo D, Zhao W, Zhao C, Zhou X (2017) OCIAD2 suppressed tumor growth and invasion via AKT pathway in hepatocelluar carcinoma. Carcinogenesis 38:910–919. https://doi.org/10.1093/carcin/bgx073
Xu N, Wu YP, Yin HB, Xue XY, Gou X (2018) Molecular network-based identification of competing endogenous RNAs and mRNA signatures that predict survival in prostate cancer. J Trans Med 16:274. https://doi.org/10.1186/s12967-018-1637-x
Yagi H et al (2019) Galpha13-mediated LATS1 down-regulation contributes to epithelial-mesenchymal transition in ovarian cancer. FASEB J 33:13683–13694. https://doi.org/10.1096/fj.201901278r
Yang L et al (2015) Dysregulated expression of cell surface glycoprotein CDCP1 in prostate cancer. Oncotarget 6:43743–43758. https://doi.org/10.18632/oncotarget.6193
Zhang K et al (2016) Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition. Oncogene 35:1271–1282. https://doi.org/10.1038/onc.2015.184
Zheng Y et al (2013) Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Nature 499:166–171. https://doi.org/10.1038/nature12308
Zhou L, Cai L, Guo Y, Zhang H, Wang P, Yi G, Huang Y (2019) Calotropin activates YAP through downregulation of LATS1 in colorectal cancer cells. Onco Targets Ther 12:4047–4054. https://doi.org/10.2147/ott.s200873
Funding
Not Applicable.
Author information
Authors and Affiliations
Contributions
NX, XYX, and XG conceived and designed the experiments; NX and HBY performed the experiments; YPW, SHC, and XDL analyzed the data; XG contributed reagents/materials/analysis tools; NX, YPW, and XG wrote the paper. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments.
Informed consent
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Xu, N., Wu, YP., Yin, HB. et al. SHCBP1 promotes tumor cell proliferation, migration, and invasion, and is associated with poor prostate cancer prognosis. J Cancer Res Clin Oncol 146, 1953–1969 (2020). https://doi.org/10.1007/s00432-020-03247-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-020-03247-1