Abstract
Recurrence within 6 months of the last round of chemotherapy is clinically defined as platinum-resistant ovarian cancer. Gene expression associated with early recurrence may provide insights into platinum resistant recurrence. Prior studies identified a 14-gene model that accurately predicted early or late recurrence in 86% of patients. One of the genes identified was CC2D1A (encoding coiled-coil and C2 domain containing 1A), which showed higher expression in tumors from patients with early recurrence. Here, we show that CC2D1A protein expression was higher in cisplatin-resistant ovarian cancer cell lines compared to cisplatin-sensitive cell lines. In addition, immunohistochemical analysis of patient tumors on a tissue microarray (n = 146) showed that high levels of CC2D1A were associated with a significantly worse overall and progression-free survival (p = 0.0002 and p = 0.006, respectively). To understand the contribution of CC2D1A in chemoresistance, we generated shRNA-mediated knockdown of CC2D1A in SKOV3ip and PEO4 cell lines. Cell death and clonogenic assays of these isogenic clonal lines clearly showed that downregulation of CC2D1A resulted in increased sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Moreover, nude mice bearing SKOV3ip xenografts with stably downregulated CC2D1A were more sensitive to chemotherapy as evidenced by a significantly longer survival time compared to xenografts derived from cells stably transduced with non-targeting shRNA. These results suggest CC2D1A promotes chemotherapy resistance in ovarian cancer.
Highlights
The American Cancer Society estimates 22,500 women will be diagnosed with ovarian cancer in the United States with 14,000 deaths attributed to this disease in 2019
The objective of the present study is to investigate if CC2D1A, one of the constituents of the 14-gene panel predicting early recurrence in ovarian cancer, modulates chemotherapy resistance in ovarian cancer
Western blot analysis detected the presence of CC2D1A at 100 kDa in various ovarian cancer cell lines (Figure 1A)
Summary
The American Cancer Society estimates 22,500 women will be diagnosed with ovarian cancer in the United States with 14,000 deaths attributed to this disease in 2019. This has not significantly changed from recent past estimates [1] and only slightly decreased from 16,100 estimated deaths about 15 years ago [2]. These statistics support the fact that amongst the common cancers of the reproductive tract in women, ovarian cancer carries the highest mortality rates. A large fraction of the patients who initially respond to chemotherapy eventually relapse, develop resistance to chemotherapy, and die of their disease after receiving several different chemotherapy regimens
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