Annexin A4 is involved in proliferation, chemo-resistance and migration and invasion in ovarian clear cell adenocarcinoma cells.
Ovarian clear cell adenocarcinoma (CCC) is the second most common subtype of ovarian cancer after high-grade serous 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 isoelectric points (IEPs) that are upregulated in CCC cell lines. Although several in vitro investigations have shown ANXA4 to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpression in cells other than CCC. To elucidate the function of the ANXA4 in CCC cells, we established CCC cell lines whose ANXA4 expressions are stably knocked down. Two parental cells were used: OVTOKO contains almost exclusively an acidic subtype of ANXA4, and OVISE contains predominantly a basic subtype but also a detectable acidic subtype. ANXA4 knockdown (KO) resulted in significant growth retardation and greater sensitivity to carboplatin in OVTOKO cells. ANXA4-KO caused significant loss of migration and invasion capability in OVISE cells, but this effect was not seen in OVTOKO cells. We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samples in ratios that vary by patient. Further investigation to clarify the mechanism that produces the subtypes is needed to clarify the function of ANXA4 in CCC, and might allow stratification and improved treatment strategies for patients with CCC.
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan ; Department of Obstetrics and Gynecology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Tae
T
Mogami
Naho
N
Yokota
Mikiko
M
Asai-Sato
Roppei
R
Yamada
Shiro
S
Koizume
Yuji
Y
Sakuma
Mitsuyo
M
Yoshihara
Yoshiyasu
Y
Nakamura
Yasuo
Y
Takano
Fumiki
F
Hirahara
Yohei
Y
Miyagi
Etsuko
E
Miyagi
D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017314:Annexin A4 / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D007526:Isoelectric Point; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis
D017314:Annexin A4; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; C098946:hyaluronan-mediated motility receptor