Skip to main content
Log in

Roles of flotillins in tumors

脂筏标记蛋白flotillins 在肿瘤中的研究进展

  • Review
  • Published:
Journal of Zhejiang University-SCIENCE B Aims and scope Submit manuscript

Abstract

The identification and use of molecular biomarkers have greatly improved the diagnosis and treatment of malignant tumors. However, a much deeper understanding of oncogenic proteins is needed for the benefit to cancer patients. The lipid raft marker proteins, flotillin-1 and flotillin-2, were first found in goldfish retinal ganglion cells during axon regeneration. They have since been found in a variety of cells, mainly on the inner surface of cell membranes, and not only act as a skeleton to provide a platform for protein–protein interactions, but also are involved in signal transduction, nerve regeneration, endocytosis, and lymphocyte activation. Previous studies have shown that flotillins are closely associated with tumor development, invasion, and metastasis. In this article, we review the functions of flotillins in relevant cell processes, their underlying mechanisms of action in a variety of tumors, and their potential applications to tumor molecular diagnosis and targeted therapy.

概要

本文旨在对flotillins 在相关细胞进程中的作用、 在多种肿瘤中的作用和机制及其在肿瘤分子诊 断和靶向治疗等方面的潜在应用价值进行综述。 图1 以示意图的形式直观地展示flotillin-1 和 flotillin-2 的蛋白结构;表1 对flotillin-1 和 flotillin-2 在各种肿瘤中的表达异常情况、发挥的 生物学功能及其机制进行汇总;在图2 中,以模 式图的形式展示flotillin-1 和flotillin-2 在肿瘤细 胞中参与的信号通路及导致肿瘤细胞出现的不 同表型。许多研究表明,flotillins 在多种肿瘤中 过表达,并且与肿瘤的发生发展、分期和转移密 切相关。转移标志着肿瘤由局部病变发展为不可 治愈的系统病变,是肿瘤预后的一个重要影响因 素,但是其机制尚未完全阐述。因此,对其机制 进行进一步探索有助于促进恶性肿瘤分子诊断、 预后和精准治疗的发展。

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Affentranger S, Martinelli S, Hahn J, et al., 2011. Dynamic reorganization of flotillins in chemokine-stimulated human T-lymphocytes. BMC Cell Biol, 12:28. https://doi.org/10.1186/1471-2121-12-28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ait-Slimane T, Galmes R, Trugnan G, et al., 2009. Basolateral internalization of GPI-anchored proteins occurs via a clathrin-independent flotillin-dependent pathway in polarized hepatic cells. Mol Biol Cell, 20(17):3792–3800. https://doi.org/10.1091/mbc.E09-04-0275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amaddii M, Meister M, Banning A, et al., 2012. Flotillin-1/ reggie-2 protein plays dual role in activation of receptortyrosine kinase/mitogen-activated protein kinase signaling. J Biol Chem, 287(10):7265–7278. https://doi.org/10.1074/jbc.M111.287599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Asp N, Pust S, Sandvig K, 2014. Flotillin depletion affects ErbB protein levels in different human breast cancer cells. Biochim Biophys Acta, 1843(9):1987–1996. https://doi.org/10.1016/j.bbamcr.2014.04.013

    Article  CAS  PubMed  Google Scholar 

  • Babuke T, Ruonala M, Meister M, et al., 2009. Heterooligomerization of reggie-1/flotillin-2 and reggie-2/ flotillin-1 is required for their endocytosis. Cell Signal, 21(8):1287–1297. https://doi.org/10.1016/j.cellsig.2009.03.012

    Article  CAS  PubMed  Google Scholar 

  • Banning A, Regenbrecht CRA, Tikkanen R, 2014. Increased activity of mitogen activated protein kinase pathway in flotillin-2 knockout mouse model. Cell Signal, 26(2): 198–207. https://doi.org/10.1016/j.cellsig.2013.11.001

    Article  CAS  PubMed  Google Scholar 

  • Baumann CA, Ribon V, Kanzaki M, et al., 2000. CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature, 407(6801):202–207. https://doi.org/10.1038/35025089

    Article  CAS  PubMed  Google Scholar 

  • Berger T, Ueda T, Arpaia E, et al., 2013. Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model. Oncogene, 32(41):4989–4994. https://doi.org/10.1038/onc.2012.499

    Article  CAS  PubMed  Google Scholar 

  • Bickel PE, Scherer PE, Schnitzer JE, et al., 1997. Flotillin and epidermal surface antigen define a new family of caveolaeassociated integral membrane proteins. J Biol Chem, 272(21):13793–13802.

    Article  CAS  PubMed  Google Scholar 

  • Bitsikas V, Riento K, Howe JD, et al., 2014. The role of flotillins in regulating Aß production, investigated using flotillin 1-/-, flotillin 2-/-double knockout mice. PLoS ONE, 9(1):e85217. https://doi.org/10.1371/journal.pone.0085217

    Article  PubMed  PubMed Central  Google Scholar 

  • Cao K, Xie D, Cao P, et al., 2014. SiRNA-mediated flotillin-2 (Flot2) downregulation inhibits cell proliferation, migration, and invasion in gastric carcinoma cells. Oncol Res, 21(5):271–279. https://doi.org/10.3727/096504014X13946737557031

    Article  CAS  PubMed  Google Scholar 

  • Cho YJ, Chema D, Moskow JJ, et al., 1995. Epidermal surface antigen (MS17S1) is highly conserved between mouse and human. Genomics, 27(2):251–258. https://doi.org/10.1006/geno.1995.1039

    Article  CAS  PubMed  Google Scholar 

  • Cremona ML, Matthies HJ, Pau K, et al., 2011. Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT. Nat Neurosci, 14(4): 469–477. https://doi.org/10.1038/nn.2781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Gassart A, Géminard C, Février B, et al., 2003. Lipid raftassociated protein sorting in exosomes. Blood, 102(13): 4336–4344. https://doi.org/10.1182/blood-2003-03-0871

    Article  PubMed  Google Scholar 

  • Dermine JF, Duclos S, Garin J, et al., 2001. Flotillin-1-enriched lipid raft domains accumulate on maturing phagosomes. J Biol Chem, 276(21):18507–18512. https://doi.org/10.1074/jbc.M101113200

    Article  CAS  PubMed  Google Scholar 

  • Doherty SD, Prieto VG, George S, et al., 2006. High flotillin-2 expression is associated with lymph node metastasis and Breslow depth in melanoma. Melanoma Res, 16(5):461–463. https://doi.org/10.1097/01.cmr.0000222592.75858.20

    Article  PubMed  Google Scholar 

  • Edgar AJ, Polak JM, 2001. Flotillin-1: gene structure: cDNA cloning from human lung and the identification of alternative polyadenylation signals. Int J Biochem Cell Biol, 33(1):53–64. https://doi.org/10.1016/S1357-2725(00)00069-8

    Article  CAS  PubMed  Google Scholar 

  • Fecchi K, Volonte D, Hezel MP, et al., 2006. Spatial and temporal regulation of GLUT4 translocation by flotillin-1 and caveolin-3 in skeletal muscle cells. FASEB J, 20(6): 705–707. https://doi.org/10.1096/fj.05-4661fje

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galbiati F, Volonté D, Goltz JS, et al., 1998. Identification, sequence and developmental expression of invertebrate flotillins from Drosophila melanogaster. Gene, 210(2): 229–237. https://doi.org/10.1016/S0378-1119(98)00064-X

    Article  CAS  PubMed  Google Scholar 

  • Gao W, Xu J, Wang F, et al., 2015. Plasma membrane proteomic analysis of human gastric cancer tissues: revealing flotillin 1 as a marker for gastric cancer. BMC Cancer, 15(1):367. https://doi.org/10.1186/s12885-015-1343-5

    Article  PubMed  PubMed Central  Google Scholar 

  • Gómez V, Sesé M, Santamaría A, et al., 2010. Regulation of Aurora B kinase by the lipid raft protein flotillin-1. J Biol Chem, 285(27):20683–20690. https://doi.org/10.1074/jbc.M110.130591

    Article  PubMed  PubMed Central  Google Scholar 

  • Hazarika P, McCarty MF, Prieto VG, et al., 2004. Up-regulation of flotillin-2 is associated with melanoma progression and modulates expression of the thrombin receptor protease activated receptor 1. Cancer Res, 64(20):7361–7369. https://doi.org/10.1158/0008-5472.CAN-04-0823

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Bray F, Center MM, et al., 2011. Global cancer statistics. CA Cancer J Clin, 61(2):69–90. https://doi.org/10.3322/caac.20107

    Article  PubMed  Google Scholar 

  • Kang M, Ren MP, Zhao L, et al., 2015. miR-485-5p acts as a negative regulator in gastric cancer progression by targeting flotillin-1. Am J Transl Res, 7(11):2212–2222.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koch JC, Solis GP, Bodrikov V, et al., 2013. Upregulation of reggie-1/flotillin-2 promotes axon regeneration in the rat optic nerve in vivo and neurite growth in vitro. Neurobiol Dis, 51:168–176. https://doi.org/10.1016/j.nbd.2012.11.007

    Article  CAS  PubMed  Google Scholar 

  • Kurrle N, Ockenga W, Meister M, et al., 2013. Phosphatidylinositol 3-kinase dependent upregulation of the epidermal growth factor receptor upon flotillin-1 depletion in breast cancer cells. BMC Cancer, 13:575. https://doi.org/10.1186/1471-2407-13-575

    Article  PubMed  PubMed Central  Google Scholar 

  • Langhorst MF, Reuter A, Luxenhofer G, et al., 2006. Preformed reggie/flotillin caps: stable priming platforms for macrodomain assembly in T cells. FASEB J, 20(6):711–713. https://doi.org/10.1096/fj.05-4760fje

    Article  CAS  PubMed  Google Scholar 

  • Leemans CR, Braakhuis BJ, Brakenhoff RH, 2011. The molecular biology of head and neck cancer. Nat Rev Cancer, 11(1):9–22. https://doi.org/10.1038/nrc2982

    Article  CAS  PubMed  Google Scholar 

  • Li H, Zhang Y, Chen SW, et al., 2014. Prognostic significance of flotillin1 expression in clinically N0 tongue squamous cell cancer. Int J Clin Exp Pathol, 7(3):996–1003.

    PubMed  PubMed Central  Google Scholar 

  • Li L, Luo J, Wang B, et al., 2013. MicroRNA-124 targets flotillin-1 to regulate proliferation and migration in breast cancer. Mol Cancer, 12:163. https://doi.org/10.1186/1476-4598-12-163

    Article  PubMed  PubMed Central  Google Scholar 

  • Li Z, Yang Y, Gao Y, et al., 2015. Elevated expression of flotillin-1 is associated with lymph node metastasis and poor prognosis in early-stage cervical cancer. Am J Cancer Res, 6(1):38–50.

    PubMed  PubMed Central  Google Scholar 

  • Lin C, Wu Z, Lin X, et al., 2011. Knockdown of FLOT1 impairs cell proliferation and tumorigenicity in breast cancer through upregulation of FOXO3a. Clin Cancer Res, 17(10):3089–3099. https://doi.org/10.1158/1078-0432.CCR-10-3068

    Article  CAS  PubMed  Google Scholar 

  • Liu J, DeYoung SM, Zhang M, et al., 2005. The stomatin/prohibitin/flotillin/HflK/C domain of flotillin-1 contains distinct sequences that direct plasma membrane localization and protein interactions in 3T3-L1 adipocytes. J Biol Chem, 280(16):16125–16134. https://doi.org/10.1074/jbc.M500940200

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Huang W, Ren C, et al., 2015. Flotillin-2 promotes metastasis of nasopharyngeal carcinoma by activating NF-κB and PI3K/Akt3 signaling pathways. Sci Rep, 5: 11614. https://doi.org/10.1038/srep11614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu R, Xie H, Luo C, et al., 2015. Identification of FLOT2 as a novel target for microRNA-34a in melanoma. J Cancer Res Clin Oncol, 141(6):993–1006. https://doi.org/10.1007/s00432-014-1874-1

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Lin L, Huang Z, et al., 2015. High expression of flotillin-2 is associated with poor clinical survival in cervical carcinoma. Int J Clin Exp Pathol, 8(1):622–628.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ludwig A, Otto GP, Riento K, et al., 2010. Flotillin microdomains interact with the cortical cytoskeleton to control uropod formation and neutrophil recruitment. J Cell Biol, 191(4):771–781. https://doi.org/10.1083/jcb.201005140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mao L, Hong WK, Papadimitrakopoulou VA, 2004. Focus on head and neck cancer. Cancer Cell, 5(4):311–316. https://doi.org/10.1016/S1535-6108(04)00090-X

    Article  CAS  PubMed  Google Scholar 

  • Mitra P, Zheng X, Czech MP, 2004. RNAi-based analysis of CAP, Cbl, and CrkII function in the regulation of GLUT4 by insulin. J Biol Chem, 279(36):37431–37435. https://doi.org/10.1074/jbc.C400180200

    Article  CAS  PubMed  Google Scholar 

  • Morrow IC, Parton RG, 2005. Flotillins and the PHB domain protein family: rafts, worms and anaesthetics. Traffic, 6(9):725–740. https://doi.org/10.1111/j.1600-0854.2005.00318.x

    Article  CAS  PubMed  Google Scholar 

  • Munderloh C, Solis GP, Bodrikov V, et al., 2009. Reggies/flotillins regulate retinal axon regeneration in the zebrafish optic nerve and differentiation of hippocampal and N2a neurons. J Neurosci, 29(20):6607–6615. https://doi.org/10.1523/JNEUROSCI.0870-09.2009

    Article  CAS  PubMed  Google Scholar 

  • Perou CM, Sørlie T, Eisen MB, et al., 2000. Molecular portraits of human breast tumours. Nature, 406(6797): 747–752. https://doi.org/10.1038/35021093

    Article  CAS  PubMed  Google Scholar 

  • Punyadeera C, Dassen H, Klomp J, et al., 2005. Oestrogenmodulated gene expression in the human endometrium. Cell Mol Life Sci, 62(2):239–250. https://doi.org/10.1007/s00018-004-4435-y

    Article  CAS  PubMed  Google Scholar 

  • Pust S, Klokk TI, Musa N, et al., 2013. Flotillins as regulators of ErbB2 levels in breast cancer. Oncogene, 32(29): 3443–3451. https://doi.org/10.1038/onc.2012.357

    Article  CAS  PubMed  Google Scholar 

  • Rivera-Milla E, Stuermer CA, Málaga-Trillo E, 2006. Ancient origin of reggie (flotillin), reggie-like, and other lipid-raft proteins: convergent evolution of the SPFH domain. Cell Mol Life Sci, 63(3):343–357. https://doi.org/10.1007/s00018-005-5434-3

    Article  CAS  PubMed  Google Scholar 

  • Santamaria A, Castellanos E, Gómez V, et al., 2005. PTOV1 enables the nuclear translocation and mitogenic activity of flotillin-1, a major protein of lipid rafts. Mol Cell Biol, 25(5):1900–1911. https://doi.org/10.1128/MCB.25.5.1900-1911.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saslowsky DE, Cho JA, Chinnapen H, et al., 2010. Intoxication of zebrafish and mammalian cells by cholera toxin depends on the flotillin/reggie proteins but not Derlin-1 or -2. J Clin Invest, 120(12):4399–4409. https://doi.org/10.1172/JCI42958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Satyamoorthy K, Li G, Gerrero MR, et al., 2003. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res, 63(4):756–759.

    CAS  PubMed  Google Scholar 

  • Schroeder WT, Stewart-Galetka S, Mandavilli S, et al., 1994. Cloning and characterization of a novel epidermal cell surface antigen (ESA). J Biol Chem, 269(31):19983–19991.

    CAS  PubMed  Google Scholar 

  • Schulte T, Paschke KA, Laessing U, et al., 1997. Reggie-1 and reggie-2, two cell surface proteins expressed by retinal ganglion cells during axon regeneration. Development, 124(2):577–587.

    CAS  PubMed  Google Scholar 

  • Siegel R, Naishadham D, Jemal A, 2013. Cancer statistics, 2013. CA Cancer J Clin, 63(1):11–30. https://doi.org/10.3322/caac.21166

    Article  PubMed  Google Scholar 

  • Song L, Gong H, Lin C, et al., 2012. Flotillin-1 promotes tumor necrosis factor-a receptor signaling and activation of NF-?B in esophageal squamous cell carcinoma cells. Gastroenterology, 143(4):995–1005.e12. https://doi.org/10.1053/j.gastro.2012.06.033

    Article  CAS  PubMed  Google Scholar 

  • Stuermer CA, 2010. The reggie/flotillin connection to growth. Trends Cell Biol, 20(1):6–13. https://doi.org/10.1016/j.tcb.2009.10.003

    Article  CAS  PubMed  Google Scholar 

  • Stuermer CA, 2012. How reggies regulate regeneration and axon growth. Cell Tissue Res, 349(1):71–77. https://doi.org/10.1007/s00441-012-1343-6

    Article  CAS  PubMed  Google Scholar 

  • Takano N, Iizuka N, Hazama S, et al., 2002. Expreßsion of estrogen receptor-a and -ß mRNAs in human gastric cancer. Cancer Lett, 176(2):129–135. https://doi.org/10.1016/S0304-3835(01)00739-X

    Article  CAS  PubMed  Google Scholar 

  • Vincent-Chong VK, Salahshourifar I, Karen-Ng LP, et al., 2014. Overexpression of MMP13 is associated with clinical outcomes and poor prognosis in oral squamous cell carcinoma. Sci World J, 2014:897523. https://doi.org/10.1155/2014/897523

    Article  Google Scholar 

  • Wang X, Yang Q, Guo L, et al., 2013. Flotillin-2 is associated with breast cancer progression and poor survival outcomes. J Transl Med, 11(1):190. https://doi.org/10.1186/1479-5876-11-190

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang YL, Yao WJ, Guo L, et al., 2015. Expression of flotillin-2 in human non-small cell lung cancer and its correlation with tumor progression and patient survival. Int J Clin Exp Pathol, 8(1):601–607.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wen Q, Li J, Wang W, et al., 2014. Increased expression of flotillin-2 protein as a novel biomarker for lymph node metastasis in nasopharyngeal carcinoma. PLoS ONE, 9(7):e101676. https://doi.org/10.1371/journal.pone.0101676

    Article  PubMed  PubMed Central  Google Scholar 

  • Xie G, Li J, Chen J, et al., 2015. Knockdown of flotillin-2 impairs the proliferation of breast cancer cells through modulation of Akt/FOXO signaling. Oncol Rep, 33(5): 2285–2290. https://doi.org/10.3892/or.2015.3826

    Article  CAS  PubMed  Google Scholar 

  • Xie S, Xu H, Shan X, et al., 2015. Clinicopathological and prognostic significance of survivin expression in patients with oral squamous cell carcinoma: evidence from a meta-analysis. PLoS ONE, 10(2):e0116517. https://doi.org/10.1371/journal.pone.0116517

    Article  PubMed  PubMed Central  Google Scholar 

  • Yan Y, Yang FQ, Zhang HM, et al., 2014. Up-regulation of flotillin-2 is associated with renal cell carcinoma progression. Tumor Biol, 35(10):10479–10486. https://doi.org/10.1007/s13277-014-2343-9

    Article  CAS  Google Scholar 

  • Yang XY, Ren CP, Wang L, et al., 2005. Identification of differentially expressed genes in metastatic and nonmetastatic nasopharyngeal carcinoma cells by suppression subtractive hybridization. Cell Oncol, 27(4):215–223. https://doi.org/10.1155/2005/108490

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zagouri F, Sergentanis TN, Chrysikos D, et al., 2012. Molecularly targeted therapies in cervical cancer. A systematic review. Gynecol Oncol, 126(2):291–303. https://doi.org/10.1016/j.ygyno.2012.04.007

    Article  CAS  PubMed  Google Scholar 

  • Zhang SH, Wang CJ, Shi L, et al., 2013. High expression of FLOT1 is associated with progression and poor prognosis in hepatocellular carcinoma. PLoS ONE, 8(6):e64709. https://doi.org/10.1371/journal.pone.0064709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Li H, Han J, et al., 2015. Down-regulation of microRNA-124 is correlated with tumor metastasis and poor prognosis in patients with lung cancer. Int J Clin Exp Pathol, 8(2):1967–1972.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao L, Lin L, Pan C, et al., 2015. Flotillin-2 promotes nasopharyngeal carcinoma metastasis and is neceßsary for the epithelial-mesenchymal transition induced by transforming growth factor-ß. Oncotarget, 6(12):9781–9793. https://doi.org/10.18632/oncotarget.3382

    PubMed  PubMed Central  Google Scholar 

  • Zhu Z, Wang J, Sun Z, et al., 2013. Flotillin2 expression correlates with HER2 levels and poor prognosis in gastric cancer. PLoS ONE, 8(5):e62365. https://doi.org/10.1371/journal.pone.0062365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Cai-ping Ren.

Additional information

Project supported by the National Natural Science Foundation of China (Nos. 81773179 and 81272972), the National Basic Research Program (973) of China (No. 2010CB833605), the Hunan Provincial Science and Technology Department (Nos. 2013FJ4010 and 2014FJ6006), the Open-End Fund for the Valuable and Precision Instruments of Central South University (Nos. CSUZC201634 and CSUZC201638), the Natural Science Foundation of Hunan Province (No. 2016JJ2172), and the National College Students Innovation Projects (Nos. 201610533264 and 201610533538), China

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Xx., Liu, Wd., Wang, L. et al. Roles of flotillins in tumors. J. Zhejiang Univ. Sci. B 19, 171–182 (2018). https://doi.org/10.1631/jzus.B1700102

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1631/jzus.B1700102

Keywords

CLC number

关键词

Navigation