title: Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3-CTTN-Akt pathway in esophageal squamous cell carcinoma.
abstract: We have shown earlier that overexpression of Calreticulin (CRT) contributed to a poor prognosis for patients with esophageal squamous cell carcinoma (ESCC). Here, we have shown an important role of CRT in tumorigenesis through enhancing cell motility and anoikis resistance. SiRNA-mediated knockdown of CRT caused impaired cell migration, invasion and resistance to anoikis. Notably, CRT downregulation decreased the expression of Cortactin (CTTN), which has been previously reported as a candidate oncogene associated with anoikis through the PI3K-Akt pathway. In addition, Akt phosphorylation was abolished after CRT downregulation and its activation can be refreshed by CRT upregulation, suggesting that CRT-enhanced cell resistance to anoikis through the CRT-CTTN-PI3K-Akt pathway. Moreover, the CTTN mRNA level was decreased in CRT-siRNA cells, coupled with the inactivation of STAT3. Expression of both CTTN and p-STAT3 was reduced in tumor cells following incubation with the JAK-specific inhibitor, AG490. Chromatin immunoprecipitation assay showed direct binding of p-STAT3 to the conservative STAT3-binding sequences in CTTN promoter. Furthermore, overexpression of CTTN in CRT-downregulated ESCC cells restored its motility and resistance to anoikis. This study not only reveals a role of CRT in motility promotion and anoikis resistance in ESCC cells, but also identifies CRT as an upstream regulator in the CRT-STAT3-CTTN-Akt pathway.
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: X-L
authors.initials: XL
authors.lastname: Du
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: S-G
authors.initials: SG
authors.lastname: Liu
authors.forename: M-L
authors.initials: ML
authors.lastname: Luo
authors.forename: J-J
authors.initials: JJ
authors.lastname: Hao
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: D-C
authors.initials: DC
authors.lastname: Lin
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: Y
authors.initials: Y
authors.lastname: Cai
authors.forename: Q-M
authors.initials: QM
authors.lastname: Zhan
authors.forename: M-R
authors.initials: MR
authors.lastname: Wang
mesh_terms: D000362:Agar; D000818:Animals; D023102:Anoikis; D037282:Calreticulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C495868:CTTN protein, human; D037282:Calreticulin; D051356:Cortactin; D050796:STAT3 Transcription Factor; D000362:Agar; D051057:Proto-Oncogene Proteins c-akt
references.citation: J BUON. 2008 Jan-Mar;13(1):101-7
references.pmid: 18404795
references.citation: Int J Oncol. 2005 Nov;27(5):1425-31
references.pmid: 16211239
references.citation: J Hepatol. 2004 Oct;41(4):629-36
references.pmid: 15464244
references.citation: Pathol Oncol Res. 2009 Mar;15(1):89-90
references.pmid: 18925427
references.citation: J Cell Biol. 1997 Feb 10;136(3):555-65
references.pmid: 9024687
references.citation: Oncogene. 1999 Aug 5;18(31):4440-9
references.pmid: 10442635
references.citation: Mol Cell Biochem. 2004 Apr;259(1-2):23-33
references.pmid: 15124904
references.citation: Mol Biol Cell. 2004 Apr;15(4):1862-70
references.pmid: 14767071
references.citation: Proteomics. 2006 Feb;6(3):1011-8
references.pmid: 16400690
references.citation: Cancer Lett. 2008 Jul 8;265(2):157-66
references.pmid: 18406052
references.citation: Cancer Res. 2006 Sep 1;66(17):8662-71
references.pmid: 16951181
references.citation: Exp Cell Res. 2000 Apr 10;256(1):105-11
references.pmid: 10739657
references.citation: Cell Death Differ. 2004 Mar;11(3):321-30
references.pmid: 14685164
references.citation: Cancer Res. 2006 Dec 15;66(24):11690-9
references.pmid: 17178864
references.citation: J Biol Chem. 2001 Mar 9;276(10):7327-36
references.pmid: 11084024
references.citation: Nature. 1997 Apr 24;386(6627):843-7
references.pmid: 9126744
references.citation: J Biol Chem. 2002 May 31;277(22):19255-64
references.pmid: 11907032
references.citation: Oncogene. 2009 Jan 22;28(3):431-44
references.pmid: 18931703
references.citation: J Mol Med (Berl). 2007 Aug;85(8):863-75
references.pmid: 17318615
references.citation: J Investig Dermatol Symp Proc. 2006 Sep;11(1):57-65
references.pmid: 17069011
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13312-7
references.pmid: 15326310
references.citation: Proteomics. 2002 Sep;2(9):1220-8
references.pmid: 12362339
references.citation: Exp Cell Res. 1997 Jan 10;230(1):50-60
references.pmid: 9013706
references.citation: Anal Cell Pathol. 2000;21(1):1-9
references.pmid: 11254220
references.citation: FASEB J. 2008 Nov;22(11):3968-79
references.pmid: 18653767
references.citation: Cancer Res. 2001 Sep 15;61(18):6906-11
references.pmid: 11559568
references.citation: Cancer Res. 2006 Aug 15;66(16):8017-25
references.pmid: 16912177
references.citation: FEBS Lett. 2005 Jan 31;579(3):577-85
references.pmid: 15670811
references.citation: J Biol Chem. 2005 Jun 10;280(23):22425-36
references.pmid: 15817475
references.citation: Curr Biol. 2003 Mar 4;13(5):384-93
references.pmid: 12620186
references.citation: J Biol Chem. 1996 Nov 15;271(46):29436-45
references.pmid: 8910610
references.citation: Mol Cells. 2008 May 31;25(3):390-6
references.pmid: 18443415
references.citation: Oncogene. 2009 Jan 22;28(3):445-60
references.pmid: 18850005
references.citation: Electrophoresis. 1997 Dec;18(15):2832-41
references.pmid: 9504817
references.citation: Biochem J. 1999 Dec 1;344 Pt 2:281-92
references.pmid: 10567207
references.citation: J Biol Chem. 2006 Oct 27;281(43):32469-84
references.pmid: 16943193
references.citation: Biochem Soc Trans. 2004 Jun;32(Pt3):421-5
references.pmid: 15157151