VAV3 Overexpressed in Cancer Stem Cells Is a Poor Prognostic Indicator in Ovarian Cancer Patients

Abstract

Ovarian carcinoma is a highly lethal malignancy due to frequent relapse and drug resistance. Cancer stem cells (CSCs) are thought to contribute significantly to disease relapse and drug resistance. In this study, a subpopulation of CSCs of ovarian carcinoma was isolated and the genes differentially expressed in these cells were identified to characterize CSCs and to find candidate biomarkers. Ovarian carcinoma cells from patients were primarily cultured, and spheroid-forming cells (SFCs) were isolated. The characteristic genes of SFCs were identified through cDNA microarray and validation by quantitative real-time polymerase chain reaction and immunohistochemistry, and the association of their expression with clinicopathologic parameters was analyzed. GSC (4.26-fold), VAV3 (7.05-fold), FOXA2 (12.06-fold), LEF1 (17.26-fold), COMP (21.33-fold), GRIN2A (9.36-fold), CD86 (23.14-fold), PYY (4.18-fold), NKX3-2 (10.35-fold), and PDK4 (74.26-fold) were significantly upregulated in SFCs compared with parental cancer cells. With validation for human ovarian carcinomas, LEF1, PYY, NKX3-2, and WNT3A were significantly upregulated in chemoresistant cancers compared with chemosensitive cancers. Overexpression of LEF1, VAV3, and NKX3-2 was significantly associated with distant metastasis by immunohistochemistry. VAV3 overexpression was an independent poor survival indicator (hazard ratio=15.27, P<0.05) by multivariate Cox analysis. The further functional assay revealed that VAV3 knockdown regulated CSC activation and ovarian cancer cell proliferation and sensitized paclitaxel (PTX)-resistant cancer cells to PTX treatment. Taken together, we identified by high-throughput analysis of CSCs that VAV3 overexpression is a novel biomarker for poor prognosis and survival in ovarian carcinoma.

Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum‐response

“…Gene array analyses revealed significant differences in expression of several genes, whereby two candidate genes, namely ABCB1 and Vav3, exhibited marked overexpression in the stem‐cell like side‐population. This finding is in line with a recent study showing that Vav3 is overexpressed in spheroid‐forming ovarian cancer cell populations expressing stem cell markers such as ALDH1, CD44 and CD133 . In our study, Vav3 protein was shown to be associated with distant metastasis and poor clinical outcome in a collective of 74 cancer specimens.…”

“…This finding is in line with a recent study showing that Vav3 is overexpressed in spheroid-forming ovarian cancer cell populations expressing stem cell markers such as ALDH1, CD44 and CD133. 45 In our study, Vav3 protein was shown to be associated with distant metastasis and poor clinical outcome in a collective of 74 cancer specimens. In our cohort full-length Vav3 was not associated with clinical outcome, whereas Vav3.1 overexpression was linked to clinicopathologically tumor variables and was also prognostically relevant.…”

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

“…Their anomalous expression and/or activation may impact patient outcome prediction and therapeutic management. For example, Vav3 overexpression in ovarian cancer associates with poor prognosis and confers resistance to established therapeutic regimes (31). Genetic alterations in the VAV1 gene, including activating mutations and fusions, have been found in peripheral T-cell lymphomas, establishing an oncogenic role for this GEF in the development of this disease (32).…”

STROBE-compliant integrin through focal adhesion involve in cancer stem cell and multidrug resistance of ovarian cancer

“…Through comprehensive integration of references about CSC and drug resistance in PubMed, we summarized 36 CSC genes significantly associated with drug resistance in ovarian cancer, which included POU5F1 , [3] ENG , [4] ABCB1 , [5] ABCG2 , [6] ALDH1A1 , [7] ARID3B , [8] PROM1 , [9] CD44 , [10] KIT , [11] MAPK1 , [12] EDNRA , [13] EZH2 , [14] TERT , [15] JAK2 , [16] KLF5 , [17] LIN28A , [18] MMP2 , [19] MYD88 , [20] NACC1 , [21] NANOG , [22] NFKB1 , [23] NOTCH3 , [24] TP53 , [25] PIK3CA , [26] SOX2 , [27] TLR2 , [28] TWIST1 , [29] VAV3 , [30] WG , [7] XIAP , [31] YAP1 , [32] FLT4 , [33] NES , [34] CD24 , [35] WWOX , [36] and DDB2 . [37] …”

“…However, cisplatin resistance is a serious issue that greatly affects the survival of patients. Several studies have found the evidence of the existence of CSC in many tumors, such as pancreatic cancer, [40] ovarian cancer, [30] and liver cancer. [41] CSCs are the origins of variety of cancer cells, they can be primary resistance to the traditional treatment or acquired resistance after the initial treatment.…”