Annexin A4 Is Involved in Proliferation, Chemo-Resistance and Migration and Invasion in Ovarian Clear Cell Adenocarcinoma Cells.docVIP

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Annexin A4 Is Involved in Proliferation, Chemo-Resistance and Migration and Invasion in Ovarian Clear Cell Adenocarcinoma Cells.doc

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Annexin A4 Is Involved in Proliferation, Chemo-Resistance and Migration and Invasion in Ovarian Clear Cell Adenocarcinoma Cells

AnnexinA4IsInvolvedinProliferation,Chemo- ResistanceandMigrationandInvasioninOvarianClear CellAdenocarcinomaCells TaeMogami1,2.,NahoYokota2.,MikikoAsai-Sato2,RoppeiYamada1,ShiroKoizume1,YujiSakuma1, MitsuyoYoshihara1,YoshiyasuNakamura1,YasuoTakano1,FumikiHirahara2,YoheiMiyagi1*, EtsukoMiyagi2* 1MolecularPathologyandGeneticsDivision,KanagawaCancerCenterResearchInstitute,Yokohama,Japan,2DepartmentofObstetricsandGynecology,YokohamaCity UniversityGraduateSchoolofMedicine,Yokohama,Japan Abstract Ovarianclearcelladenocarcinoma(CCC)isthesecondmostcommonsubtypeofovariancancerafterhigh-gradeserous adenocarcinomas. CCC tends to develop resistance to the standard platinum-based chemotherapy, and has a poor prognosis when diagnosed in advanced stages. The ANXA4 gene, along with its product, a Ca -binding annexin A4 ++ (ANXA4) protein, has been identified as the CCC signature gene. We reported two subtypes of ANXA4 with different isoelectricpoints(IEPs)thatareupregulatedinCCCcelllines.AlthoughseveralinvitroinvestigationshaveshownANXA4to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpressionincellsotherthanCCC.ToelucidatethefunctionoftheANXA4inCCCcells,weestablishedCCCcelllines whoseANXA4expressionsarestablyknockeddown.Twoparentalcellswereused:OVTOKOcontainsalmostexclusivelyan acidicsubtypeofANXA4,andOVISEcontainspredominantlyabasicsubtypebutalsoadetectableacidicsubtype.ANXA4 knockdown(KO)resultedinsignificantgrowthretardationandgreatersensitivitytocarboplatininOVTOKOcells.ANXA4-KO causedsignificantlossofmigrationandinvasioncapabilityinOVISEcells,butthiseffectwasnotseeninOVTOKOcells.We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samplesinratiosthatvarybypatient.Furtherinvestigationtoclarifythemechanismthatproducesthesubtypesisneeded toclarifythefunctionofANXA4inCCC,andmightallowstratificationandimprovedtreatmentstrategiesforpatie