Annexin A2 and S100A10 are independent predictors of serous ovarian cancer outcome

Annexin A2, a calcium phospholipid binding protein, has been shown to play an important role in ovarian cancer metastasis. This study examined whether annexin A2 and S100A10 can be used as prognostic markers in serous ovarian cancer. ANXA2 and S100A10 gene expressions were assessed in publicly available ovarian cancer data sets and annexin A2 and S100A10 protein expressions were assessed by immunohistochemistry in a uniform cohort of stage III serous ovarian cancers (n = 109). Kaplan-Meier and Cox regression analyses were performed to assess the relationship between annexin A2 or S100A10 messenger RNA (mRNA) and protein expressions with clinical outcome. High ANXA2 mRNA levels in stage III serous ovarian cancers were associated with reduced progression-free survival (PFS; P = 0.023) and overall survival (OS; P = 0.0038), whereas high S100A10 mRNA levels predicted reduced OS (P = 0.0019). Using The Cancer Genome Atlas data sets, ANXA2 but not S100A10 expression was associated with higher clinical stage (P = 0.005), whereas both ANXA2 and S100A10 expressions were associated with the mesenchymal molecular subtype (P < 0.0001). Kaplan-Meier and Cox regression analyses showed that high stromal annexin A2 immunostaining was significantly associated with reduced PFS (P = 0.013) and OS (P = 0.044). Moreover, high cytoplasmic S100A10 staining was significantly associated with reduced OS (P = 0.027). Multivariate Cox regression analysis showed stromal annexin A2 (P = 0.009) and cytoplasmic S100A10 (P = 0.016) levels to be independent predictors of OS. Patients with high stromal annexin A2 and high cytoplasmic S100A10 expressions had a 3.4-fold increased risk of progression (P = 0.02) and 7.9-fold risk of ovarian cancer death (P = 0.04). Our findings indicate that together annexin A2 and S100A10 expressions are powerful predictors of serous ovarian cancer outcome.

Introduction

Ovarian cancer is the most lethal gynecological cancer. Up to 70% of ovarian cancer patients are diagnosed at advanced stage (stage III and IV) with a 5-year survival rate of only 27%.¹ More than 70% of epithelial ovarian cancers represent the serous histologic subtype.² The standard treatment for ovarian cancer consists of radical debulking surgery and platinum containing chemotherapy. However, treatment outcome remains poor because of high recurrence rates and the development of chemoresistant disease.² Prognostic markers are important for predicting outcome, to guide in the management of ovarian cancer patients and aid in the development of better therapeutic targets.³

Annexin A2, a calcium phospholipid binding protein, plays an important role in tumorigenesis.⁴ We have previously shown increased stromal annexin A2 protein expression in serous ovarian cancer tissues compared with the stroma of normal ovaries, serous cystadenomas, and noninvasive borderline ovarian tumors.⁵ Moreover, depletion of annexin A2 inhibited motility and invasion of ovarian cancer cells and adhesion to the peritoneal cells in vitro. Neutralizing annexin A2 antibodies effectively inhibited ovarian cancer cell invasion in the chick chorioallantoic membrane model and ovarian tumor growth and metastasis in the intraperitoneal xenograft mouse model.⁵ Annexin A2 has been shown to be a promising prognostic biomarker in various malignancies,⁶ and high annexin A2 immunostaining was associated with poor prognosis in non-small cell lung cancer,7, 8, 9 colorectal carcinoma,10, 11 cholangiocarcinoma,¹² gastric carcinoma,13, 14 and glioma.¹⁵

S100A10, an annexin A2 binding protein, forms an annexin A2 heterotetramer on the cell surface of various tumor cells.16, 17 S100A10, also known as p11 protein, is a member of S100 protein family that has 2 EF-hand calcium binding motifs.¹⁸ S100A10 is a cytosolic protein and on binding to annexin A2, the annexin A2 heterotetramer complex translocates to the plasma membrane.¹⁹ It has been shown to play an important role in oncogenesis,¹⁷ and S100A10 protein expression has been characterized by immunohistochemistry in cancers of the bowel,²⁰ thyroid,²¹ and kidney.²² There have been limited studies that have assessed the prognostic value of annexin A2 and S100A10 in serous ovarian cancer,23, 24 the most common and lethal ovarian cancer subtype. In this study, we investigated whether messenger RNA (mRNA) and protein expressions of both annexin A2 and S100A10 have prognostic utility in a uniform cohort of stage III serous ovarian cancer.