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Nanoparticle (NP)-mediated APOC1 silencing to inhibit MAPK/ERK and NF-κB pathway and suppress breast cancer growth and metastasis

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Abstract

Breast cancer is one of the most common malignant tumors with high mortality and poor prognosis in women. There is an urgent need to discover new therapeutic targets for breast cancer metastasis. Herein, we identified that Apolipoprotein C1 (APOC1) was up-regulated in primary tumor of breast cancer patient that recurrence and metastasis by immunohistochemistry (IHC). Kaplan-Meier Plotter database showed that high levels of APOC1 in breast cancer patients were strongly associated with worse overall survival (OS) and relapse-free survival (RFS). Mechanistically, APOC1 silencing significantly inhibits MAPK/ERK kinase pathway and restrains the NF-κB to decrease the transcription of target genes related to growth and metastasis in vitro. Based on this regulatory mechanism, we developed these findings into potential therapeutic drugs, glutathione (GSH) responsive nano-particles (NPs) were used for systemic APOC1 siRNA delivery, NPs (siAPOC1) silenced APOC1 expression, and subsequently resulted in positive anti-tumor effects in orthotopic and liver metastasis models in vivo. Taken together, GSH responsive NP-mediated siAPOC1 delivery was proved to be effective in regulating growth and metastasis in multiple tumor models. These findings show that APOC1 could be a potential biomarker to predict the prognosis of breast cancer patients and NP-mediated APOC1 silencing could be new strategies for exploration of new treatments for breast cancer metastasis.

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References

  • Blache, U., Horton, E.R., Xia, T., Schoof, E.M., Blicher, L.H., Schönenberger, A., Snedeker, J.G., Martin, I., Erler, J.T., and Ehrbar, M. (2019). Mesenchymal stromal cell activation by breast cancer secretomes in bioengineered 3D microenvironments. Life Sci Alliance 2, e201900304.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bomgaars, L., Geyer, J.R., Franklin, J., Dahl, G., Park, J., Winick, N.J., Klenke, R., Berg, S.L., and Blaney, S.M. (2004). Phase I trial of intrathecal liposomal cytarabine in children with neoplastic meningitis. J Clin Oncol 22, 3916–3921.

    Article  CAS  PubMed  Google Scholar 

  • Bouillet, B., Gautier, T., Blache, D., Pais de Barros, J.P., Duvillard, L., Petit, J.M., Lagrost, L., and Vergès, B. (2014). Glycation of apolipoprotein C1 impairs its CETP inhibitory property: pathophysiological relevance in patients with type 1 and type 2 diabetes. Diabetes Care 37, 1148–1156.

    Article  CAS  PubMed  Google Scholar 

  • Bus, P., Pierneef, L., Bor, R., Wolterbeek, R., van Es, L.A., Rensen, P.C., de Heer, E., Havekes, L.M., Bruijn, J.A., Berbée, J.F., et al. (2017). Apolipoprotein C-I plays a role in the pathogenesis of glomerulosclerosis. J Pathol 241, 589–599.

    Article  CAS  PubMed  Google Scholar 

  • Cai, Z., Wang, J., Li, Y., Shi, Q., Jin, L., Li, S., Zhu, M., Wang, Q., Wong, L.L., Yang, W., et al. (2023). Overexpressed Cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors. Sci China Life Sci 66, 94–109.

    Article  CAS  PubMed  Google Scholar 

  • Cao, S., Saw, P.E., Shen, Q., Li, R., Liu, Y., and Xu, X. (2022). Reduction-responsive RNAi nanoplatform to reprogram tumor lipid metabolism and repolarize macrophage for combination pancreatic cancer therapy. Biomaterials 280, 121264.

    Article  CAS  PubMed  Google Scholar 

  • Casagrande, N., Celegato, M., Borghese, C., Mongiat, M., Colombatti, A., and Aldinucci, D. (2014). Preclinical activity of the liposomal cisplatin lipoplatin in ovarian cancer. Clin Cancer Res 20, 5496–5506.

    Article  CAS  PubMed  Google Scholar 

  • Chen, J., Yang, J., and Ding, J. (2022). Rational construction of polycystine-based nanoparticles for biomedical applications. J Mater Chem B 10, 7173–7182.

    Article  CAS  PubMed  Google Scholar 

  • Cheng, R., Feng, F., Meng, F., Deng, C., Feijen, J., and Zhong, Z. (2011). Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery. J Control Release 152, 2–12.

    Article  CAS  PubMed  Google Scholar 

  • Cui, C., Xue, Y.N., Wu, M., Zhang, Y., Yu, P., Liu, L., Zhuo, R.X., and Huang, S.W. (2013). Cellular uptake, intracellular trafficking, and antitumor efficacy of doxorubicin-loaded reduction-sensitive micelles. Biomaterials 34, 3858–3869.

    Article  CAS  PubMed  Google Scholar 

  • Din, F., Aman, W., Ullah, I., Qureshi, O.S., Mustapha, O., Shafique, S., and Zeb, A. (2017). Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int J Nanomed Volume 12, 7291–7309.

    Article  Google Scholar 

  • Eccles, S.A., and Welch, D.R. (2007). Metastasis: recent discoveries and novel treatment strategies. Lancet 369, 1742–1757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fares, J., Fares, M.Y., Khachfe, H.H., Salhab, H.A., and Fares, Y. (2020). Molecular principles of metastasis: a hallmark of cancer revisited. Sig Transduct Target Ther 5, 28.

    Article  Google Scholar 

  • Feng, X., Xu, W., Liu, J., Li, D., Li, G., Ding, J., and Chen, X. (2021). Polypeptide nanoformulation-induced immunogenic cell death and remission of immunosuppression for enhanced chemoimmunotherapy. Sci Bull 66, 362–373.

    Article  CAS  Google Scholar 

  • Feng, X., Xu, W., Xu, X., Li, G., Ding, J., and Chen, X. (2020). Cystine proportion regulates fate of polypeptide nanogel as nanocarrier for chemotherapeutics. Sci China Chem 64, 293–301.

    Article  Google Scholar 

  • Gaitanis, A., and Staal, S. (2010). Liposomal doxorubicin and nab-pacli-taxel: nanoparticle cancer chemotherapy in current clinical use. In: Grobmyer, S., and Moudgil, B., eds. Cancer Nanotechnology. Methods in Molecular Biology. New York: Humana Press. 385–392.

    Chapter  Google Scholar 

  • Ghoda, L., Lin, X., and Greene, W.C. (1997). The 90-kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of IκBα and stimulates its degradation in vitro. J Biol Chem 272, 21281–21288.

    Article  CAS  PubMed  Google Scholar 

  • Guan, X. (2015). Cancer metastases: challenges and opportunities. Acta Pharm Sin B 5, 402–418.

    Article  PubMed  PubMed Central  Google Scholar 

  • Han, Y., Fan, M., Han, D., Ge, K., Chang, J., and Zhang, J. (2022). Bacteria-based nanosystems for enhanced antitumor therapy. Sci China Life Sci 65, 438–441.

    Article  CAS  PubMed  Google Scholar 

  • Jiang, B., Jia, X., Ji, T., Zhou, M., He, J., Wang, K., Tian, J., Yan, X., and Fan, K. (2022). Ferritin nanocages for early theranostics of tumors via inflammation-enhanced active targeting. Sci China Life Sci 65, 328–340.

    Article  CAS  PubMed  Google Scholar 

  • Jong, M.C., Hofker, M.H., and Havekes, L.M. (1999). Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler Thromb Vasc Biol 19, 472–484.

    Article  CAS  PubMed  Google Scholar 

  • Karin, M., and Delhase, M. (2000). The IκB kinase (IKK) and NF-κB: key elements of proinflammatory signalling. Semin Immunol 12, 85–98.

    Article  CAS  PubMed  Google Scholar 

  • Ko, H.L., Wang, Y.S., Fong, W.L., Chi, M.S., Chi, K.H., and Kao, S.J. (2014). Apolipoprotein C1 (APOC1) as a novel diagnostic and prognostic biomarker for lung cancer: a marker phase I trial. Thorac Cancer 5, 500–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kulkarni, J.A., Witzigmann, D., Chen, S., Cullis, P.R., and van der Meel, R. (2019). Lipid nanoparticle technology for clinical translation of siRNA therapeutics. Acc Chem Res 52, 2435–2444.

    Article  CAS  PubMed  Google Scholar 

  • Lambert, A.W., Pattabiraman, D.R., and Weinberg, R.A. (2017). Emerging biological principles of metastasis. Cell 168, 670–691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leduc, V., Jasmin-Bélanger, S., and Poirier, J. (2010). APOE and cholesterol homeostasis in Alzheimer’s disease. Trends Mol Med 16, 469–477.

    Article  CAS  PubMed  Google Scholar 

  • Leone, B.A., Romero, A., Rabinovich, M.G., Vallejo, C.T., Bianco, A., Perez, J.E., Machiavelli, M., Rodriguez, R., and Alvarez, L.A. (1988). Stage IV breast cancer: clinical course and survival of patients with osseous versus extraosseous metastases at initial diagnosis. Am J Clin Oncol 11, 618–622.

    Article  CAS  PubMed  Google Scholar 

  • Li, Q., Qin, T., Bi, Z., Hong, H., Ding, L., Chen, J., Wu, W., Lin, X., Fu, W., Zheng, F., et al. (2020a). Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer. Nat Commun 11, 1456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, Y., Wu, L., Zeng, L., Zhang, Z., Wang, W., Zhang, C., and Lin, N. (2020b). ApoC1 promotes the metastasis of clear cell renal cell carcinoma via activation of STAT3. Oncogene 39, 6203–6217.

    Article  CAS  PubMed  Google Scholar 

  • Liu, B., Sun, L., Liu, Q., Gong, C., Yao, Y., Lv, X., Lin, L., Yao, H., Su, F., Li, D., et al. (2015). A cytoplasmic NF-κB interacting long noncoding RNA blocks IκB phosphorylation and suppresses breast cancer metastasis. Cancer Cell 27, 370–381.

    Article  CAS  PubMed  Google Scholar 

  • Loibl, S., Poortmans, P., Morrow, M., Denkert, C., and Curigliano, G. (2021). Breast cancer. Lancet 397, 1750–1769.

    Article  CAS  PubMed  Google Scholar 

  • McKay, G.J., Savage, D.A., Patterson, C.C., Lewis, G., McKnight, A.J., and Maxwell, A.P. (2013). Association analysis of dyslipidemia-related genes in diabetic nephropathy. PLoS ONE 8, e58472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mills, R.C. 3rd (2017). Breast cancer survivors, common markers of inflammation, and exercise: a narrative review. Breast Cancer 11, 117822341774397.

    Article  Google Scholar 

  • Mooyaart, A.L., Valk, E.J.J., van Es, L.A., Bruijn, J.A., de Heer, E., Freedman, B.I., Dekkers, O.M., and Baelde, H.J. (2011). Genetic associations in diabetic nephropathy: a meta-analysis. Diabetologia 54, 544–553.

    Article  CAS  PubMed  Google Scholar 

  • Ren, H., Chen, Z., Yang, L., Xiong, W., Yang, H., Xu, K., Zhai, E., Ding, L., He, Y., and Song, X. (2019). Apolipoprotein C1 (APOC1) promotes tumor progression via MAPK signaling pathways in colorectal cancer. Cancer Manag Res Volume 11, 4917–4930.

    Article  Google Scholar 

  • Riggio, A.I., Varley, K.E., and Welm, A.L. (2021). The lingering mysteries of metastatic recurrence in breast cancer. Br J Cancer 124, 13–26.

    Article  PubMed  Google Scholar 

  • Saw, P.E., and Song, E.W. (2020). siRNA therapeutics: a clinical reality. Sci China Life Sci 63, 485–500.

    Article  CAS  PubMed  Google Scholar 

  • Setten, R.L., Rossi, J.J., and Han, S. (2019). The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov 18, 421–446.

    Article  CAS  PubMed  Google Scholar 

  • Shi, J., Kantoff, P.W., Wooster, R., and Farokhzad, O.C. (2017). Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 17, 20–37.

    Article  CAS  PubMed  Google Scholar 

  • Stagg, R.J., Venook, A.P., Chase, J.L., Lewis, B.J., Warren, R.S., Roh, M., Mulvihill, S.J., Grobman, B.J., Rayner, A.A., and Hohn, D.C. (1991). Alternating hepatic intra-arterial floxuridine and fluorouracil: a less toxic regimen for treatment of liver metastases from colorectal cancer. J Natl Cancer Inst 83, 423–428.

    Article  CAS  PubMed  Google Scholar 

  • Steeg, P.S. (2006). Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12, 895–904.

    Article  CAS  PubMed  Google Scholar 

  • Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., and Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71, 209–249.

    Article  PubMed  Google Scholar 

  • Tong, S., Zhu, H., and Bao, G. (2019). Magnetic iron oxide nanoparticles for disease detection and therapy. Mater Today 31, 86–99.

    Article  CAS  Google Scholar 

  • Valastyan, S., and Weinberg, R.A. (2011). Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, J., Luo, B., Li, X., Lu, W., Yang, J., Hu, Y., Huang, P., and Wen, S. (2017). Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells. Cell Death Dis 8, e2887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei, L., Chen, J., and Ding, J. (2021). Sequentially stimuli-responsive anticancer nanomedicines. Nanomedicine 16, 261–264.

    Article  CAS  PubMed  Google Scholar 

  • Wei, S., and Siegal, G.P. (2018). Surviving at a distant site: The organotropism of metastatic breast cancer. Semin Diagn Pathol 35, 108–111.

    Article  PubMed  Google Scholar 

  • Whitehead, K.A., Langer, R., and Anderson, D.G. (2009). Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 8, 129–138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu, X., Wu, J., Liu, S., Saw, P.E., Tao, W., Li, Y., Krygsman, L., Yegnasubramanian, S., De Marzo, A.M., Shi, J., et al. (2018). Redox-responsive nanoparticle-mediated systemic RNAi for effective cancer therapy. Small 14, 1802565.

    Article  Google Scholar 

  • Xu, X., Wu, J., Liu, Y., Saw, P.E., Tao, W., Yu, M., Zope, H., Si, M., Victorious, A., Rasmussen, J., et al. (2017). Multifunctional envelope-type siRNA delivery nanoparticle platform for prostate cancer therapy. ACS Nano 11, 2618–2627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu, X., Wu, J., Liu, Y., Yu, M., Zhao, L., Zhu, X., Bhasin, S., Li, Q., Ha, E., Shi, J., et al. (2016). Ultra-pH-responsive and tumor-penetrating nanoplatform for targeted siRNA delivery with robust anti-cancer efficacy. Angew Chem Int Ed 55, 7091–7094.

    Article  CAS  Google Scholar 

  • Yang, G., Liu, Y., Chen, J., Ding, J., and Chen, X. (2022a). Self-adaptive nanomaterials for rational drug delivery in cancer therapy. Acc Mater Res 3, 1232–1247.

    Article  CAS  Google Scholar 

  • Yang, J., Su, T., Zou, H., Yang, G., Ding, J., and Chen, X. (2022b). Spatiotemporally targeted polypeptide nanoantidotes improve chemotherapy tolerance of cisplatin. Angew Chem Int Ed 61, e202211136.

    Article  CAS  Google Scholar 

  • Yi, J., Ren, L., Wu, J., Li, W., Zheng, X., Du, G., and Wang, J. (2019). Apolipoprotein C1 (APOC1) as a novel diagnostic and prognostic biomarker for gastric cancer. Ann Transl Med 7, 380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin, H., Kanasty, R.L., Eltoukhy, A.A., Vegas, A.J., Dorkin, J.R., and Anderson, D.G. (2014). Non-viral vectors for gene-based therapy. Nat Rev Genet 15, 541–555.

    Article  CAS  PubMed  Google Scholar 

  • Younis, M.A., Tawfeek, H.M., Abdellatif, A.A.H., Abdel-Aleem, J.A., and Harashima, H. (2022). Clinical translation of nanomedicines: challenges, opportunities, and keys. Adv Drug Deliv Rev 181, 114083.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, C., and Zhang, B. (2023). RNA therapeutics: updates and future potential. Sci China Life Sci 66, 12–30.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, Z., Cheng, W., Pan, Y., and Jia, L. (2020). An anticancer agent-loaded PLGA nanomedicine with glutathione-response and targeted delivery for the treatment of lung cancer. J Mater Chem B 8, 655–665.

    Article  PubMed  Google Scholar 

  • Zheng, P., Ding, B., Shi, R., Jiang, Z., Xu, W., Li, G., Ding, J., and Chen, X. (2021). A multichannel Ca2+ nanomodulator for multilevel mitochondrial destruction-mediated cancer therapy. Adv Mater 33, 2007426.

    Article  CAS  Google Scholar 

  • Zhou, Z., Liu, X., Zhu, D., Wang, Y., Zhang, Z., Zhou, X., Qiu, N., Chen, X., and Shen, Y. (2017). Nonviral cancer gene therapy: delivery cascade and vector nanoproperty integration. Adv Drug Deliv Rev 115, 115–154.

    Article  CAS  PubMed  Google Scholar 

  • Zuckerman, J.E., and Davis, M.E. (2015). Clinical experiences with systemically administered siRNA-based therapeutics in cancer. Nat Rev Drug Discov 14, 843–856.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81570764), Guangzhou Science and Technology Project (201807010069), Shenzhen Science and Technology Project (JCYJ20190807154205627), Guangdong Natural Science Fund (2020A1515010365), and Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translation Research of Hakka Population (2018B030322003KF01).

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Authors and Affiliations

  1. Department of Biochemistry, Molecular Cancer Research Center, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China

    Shaomin Liu & Zhonghan Yang

  2. Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan, 528200, China

    Fengqian Zhang, Yixia Liang, Xiuling Li & Phei Er Saw

  3. Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang, 421001, China

    Guo Wu & Rong Liu

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  1. Shaomin Liu
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  2. Fengqian Zhang
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Correspondence to Phei Er Saw or Zhonghan Yang.

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Liu, S., Zhang, F., Liang, Y. et al. Nanoparticle (NP)-mediated APOC1 silencing to inhibit MAPK/ERK and NF-κB pathway and suppress breast cancer growth and metastasis. Sci. China Life Sci. 66, 2451–2465 (2023). https://doi.org/10.1007/s11427-022-2329-7

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