title: High expression of small GTPase Rab3D promotes cancer progression and metastasis.
abstract: Rab GTPases control exocytic and endocytic membrane trafficking such as exosomes release. As a secretory small GTPase, Rab3D is a vital regulator for protein secretion. However, the role of Rab3D in cancer was never systematically studied. The aim of this study is to examine its function and mechanism in cancer, especially metastasis. We detected protein levels of Rab3D in nine cancer cell lines and twelve types of clinical cancer specimens. Subsequently, we established in vitro migration and in vivo orthotopic metastatic mouse models to study the role of Rab3D in tumor metastasis. Here, we reported that the expression levels of Rab3D were dysregulated in cancer cells and highly correlated with tumor malignancies in the clinical samples. Increased expressions of Rab3D led to tumor invasion in vitro and lung metastasis in vivo, whereas Rab3D knockdown suppressed the tumor cell motility. Mechanistic studies revealed that Rab3D activated intracellular the AKT/GSK3β signaling to induce the EMT process. In addition, it also regulated the extracellular secretion of Hsp90α to promote tumor cell migration and invasion. These results prove that Rab3D is a key molecule to regulate tumor metastasis, suggesting that blocking the Rab3D function can be a potential therapeutic approach for cancer metastasis.
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Xin'an
authors.initials: X
authors.lastname: Lu
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yongzhang
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000201:enzymology / Q000556:secondary*; D051379:Mice; D009367:Neoplasm Staging; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D020692:rab3 GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; C492134:RAB3D protein, human; D020692:rab3 GTP-Binding Proteins
keywords: EMT; Hsp90α; Rab3D; exosomes; tumor metastasis
references.citation: Nat Rev Cancer. 2013 Feb;13(2):97-110
references.pmid: 23344542
references.citation: N Engl J Med. 2008 Dec 25;359(26):2814-23
references.pmid: 19109576
references.citation: Med Oncol. 2015 Jan;32(1):372
references.pmid: 25428385
references.citation: Trends Pharmacol Sci. 2013 May;34(5):283-9
references.pmid: 23571046
references.citation: Genes Dev. 2012 Jun 15;26(12):1287-99
references.pmid: 22713869
references.citation: Nat Cell Biol. 2007 Jun;9(6):654-9
references.pmid: 17486113
references.citation: Nat Rev Cancer. 2013 Nov;13(11):813-20
references.pmid: 24108097
references.citation: Histol Histopathol. 2002;17(3):929-36
references.pmid: 12168804
references.citation: Nat Med. 2012 Jun;18(6):883-91
references.pmid: 22635005
references.citation: Traffic. 2010 Nov;11(11):1415-28
references.pmid: 20716109
references.citation: Mol Cell Biol. 2012 Jan;32(2):399-414
references.pmid: 22083957
references.citation: Cell. 2011 Oct 14;147(2):275-92
references.pmid: 22000009
references.citation: J Clin Invest. 2009 Jun;119(6):1420-8
references.pmid: 19487818
references.citation: Nat Cell Biol. 2004 Oct;6(10):931-40
references.pmid: 15448698
references.citation: J Cell Biol. 2006 Mar 27;172(7):973-81
references.pmid: 16567498
references.citation: J Biol Chem. 2010 Dec 17;285(51):40039-49
references.pmid: 20937816
references.citation: Cancer Res. 2010 Dec 1;70(23):9533-7
references.pmid: 21098711
references.citation: Nat Cell Biol. 2004 Jun;6(6):479-80
references.pmid: 15170457
references.citation: Nat Rev Mol Cell Biol. 2009 Aug;10(8):513-25
references.pmid: 19603039
references.citation: Cancer Res. 2008 Jun 15;68(12):4833-42
references.pmid: 18559531
references.citation: Biochem Biophys Res Commun. 2001 Jul 20;285(3):708-14
references.pmid: 11453651
references.citation: Trends Biochem Sci. 2013 May;38(5):253-62
references.pmid: 23507089
references.citation: Cell. 2010 Apr 2;141(1):52-67
references.pmid: 20371345
references.citation: BMC Cancer. 2010;10:294
references.pmid: 20553606
references.citation: Lung Cancer. 2009 Mar;63(3):360-7
references.pmid: 18687502
references.citation: Mol Biol Rep. 2014 Sep;41(9):5903-11
references.pmid: 24965146
references.citation: Biochim Biophys Acta. 2012 Mar;1823(3):730-41
references.pmid: 21982864
references.citation: J Biol Chem. 2002 May 17;277(20):18002-9
references.pmid: 11875077
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21288-93
references.pmid: 19965370
references.citation: J Transl Med. 2012;10:242
references.pmid: 23217148
references.citation: Traffic. 2014 Aug;15(8):861-78
references.pmid: 24899266
references.citation: Mol Cancer Ther. 2009 May;8(5):1055-66
references.pmid: 19435871
references.citation: Nat Rev Cancer. 2012 Jun 22;12(7):447
references.pmid: 22722393
references.citation: J Biol Chem. 2012 Nov 2;287(45):37732-44
references.pmid: 22989880
references.citation: Cancer Res. 2011 Jun 1;71(11):3792-801
references.pmid: 21478294
references.citation: Mol Cell Proteomics. 2013 Aug;12(8):2148-59
references.pmid: 23645497
references.citation: Cell Cycle. 2004 Sep;3(9):1098-100
references.pmid: 15326368
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):E2057-66
references.pmid: 22753498
references.citation: Nat Rev Immunol. 2009 Aug;9(8):581-93
references.pmid: 19498381
references.citation: Biochim Biophys Acta. 2012 Jul;1820(7):940-8
references.pmid: 22503788
references.citation: Biochim Biophys Acta. 2012 Mar;1823(3):648-55
references.pmid: 21856339
references.citation: BMC Cell Biol. 2010;11:51
references.pmid: 20602761
references.citation: Nat Cell Biol. 2010 Jan;12(1):19-30; sup pp 1-13
references.pmid: 19966785
references.citation: Nat Cell Biol. 2004 Jun;6(6):507-14
references.pmid: 15146192
references.citation: Clin Dev Immunol. 2011;2011:842849
references.pmid: 22190973
references.citation: Oncotarget. 2010 Aug;1(4):304-8
references.pmid: 21304180
references.citation: World J Gastroenterol. 2012 Apr 21;18(15):1806-13
references.pmid: 22553406
references.citation: J Cell Sci. 2012 Oct 15;125(Pt 20):4780-90
references.pmid: 22899725
references.citation: Cancer Res. 2012 Oct 1;72(19):4920-30
references.pmid: 22865453
references.citation: J Natl Cancer Inst. 2010 Jun 16;102(12):866-80
references.pmid: 20484105
references.citation: Am J Respir Cell Mol Biol. 2004 Mar;30(3):288-95
references.pmid: 12933357
references.citation: Mol Cell Biol. 2008 May;28(10):3344-58
references.pmid: 18332123
references.citation: Cancer Metastasis Rev. 2013 Dec;32(3-4):623-42
references.pmid: 23709120