RAN Nucleo-Cytoplasmic Transport and Mitotic Spindle Assembly Partners XPO7 and TPX2 Are New Prognostic Biomarkers in Serous Epithelial Ovarian Cancer

Abstract

PurposeEpithelial ovarian cancer has the highest mortality rate of all gynecological malignancies. We have shown that high RAN expression strongly correlates with high-grade and poor patient survival in epithelial ovarian cancer. However, as RAN is a small GTPase involved in two main biological functions, nucleo-cytoplasmic transport and mitosis, it is still unknown which of these functions associate with poor prognosis.MethodsTo examine the biomarker value of RAN network components in serous epithelial ovarian cancer, protein expression of six specific RAN partners was analyzed by immunohistochemistry using a tissue microarray representing 143 patients associated with clinical parameters. The RAN GDP/GTP cycle was evaluated by the expression of RANBP1 and RCC1, the mitotic function by TPX2 and IMPβ, and the nucleo-cytoplasmic trafficking function by XPO7, XPOT and IMPβ.ResultsBased on Kaplan-Meier analyses, RAN, cytoplasmic XPO7 and TPX2 were significantly associated with poor overall patient survival, and RAN and TPX2 were associated with lower disease free survival in patients with high-grade serous carcinoma. Cox regression analysis revealed that RAN and TPX2 expression were independent prognostic factors for both overall and disease free survival, and that cytoplasmic XPO7 expression was a prognostic factor for overall patient survival.ConclusionsIn this systematic study, we show that RAN and two protein partners involved in its nucleo-cytoplasmic and mitotic functions (XPO7 and TPX2, respectively) can be used as biomarkers to stratify patients based on prognosis. In particular, we reported for the first time the clinical relevance of the exportin XPO7 and showed that TPX2 expression had the strongest prognostic value. These findings suggest that protein partners in each of RAN’s functions can discriminate between different outcomes in high-grade serous epithelial ovarian cancer patients. Furthermore, these proteins point to cellular processes that may ultimately be targeted to improve the survival in serous epithelial ovarian cancer.

TPX2 in human clear cell renal carcinoma: Expression, function and prognostic significance

“…Such results have revealed the correlation between TPX2 and the tumorigenesis of cancer. In addition, it has been demonstrated that the overexpression of TPX2 serves an important role in the progression and invasion of human malignancies (21), and that its expression is associated with the aggressiveness of ovarian cancer (22). Previous studies have reported that TPX2 is involved in cell proliferation and associated with poor prognosis in patients with esophageal cell carcinoma (23,24), supporting the hypothesis that TPX2 functions as a tumor promoter in this particular type of cancer.…”

Prognostic Value of Immunohistochemical Expressions of the Stem Cell Biomarker "LGR5" and the Proliferation Biomarker "TPX2" in Colorectal Carcinoma

“…In recent years, a connection between TPX2 and initiation, progression and prognosis of malignant tumor is becoming a focus of researches [15] . Previous studies showed that abnormally high expression of TPX2 has been confirmed in many tumor tissues [16,17] . TPX2 can upregulate expression of matrix metalloproteinases (MMP) family through activating PI3K/Akt pathway.…”

“…It has been found that elevated expression of TPX2 promotes tumor growth in pancreatic cancer [39] . Also, high levels of TPX2 expression are correlated with the aggressiveness of ovarian and salivary gland cancers [17,40] .…”

Tyrosine Phosphatase PTPRJ/DEP-1 Is an Essential Promoter of Vascular Permeability, Angiogenesis, and Tumor Progression

“…Tumors were fixed in formaldehyde (3.7%, v/v) and embedded in paraffin, or lysed in RIPA buffer, and then processed for IHC (two slices/ tumor) or Western blotting, respectively (31,32). For pY 418 Src and CD31 immunofluorescence, paraffin-embedded tumor slices were dewaxed, subjected to antigen retrieval, and incubated with primary antibodies using the BenchMark XT automated stainer (Ventana Medical System Inc.; ref.…”

“…For pY 418 Src and CD31 immunofluorescence, paraffin-embedded tumor slices were dewaxed, subjected to antigen retrieval, and incubated with primary antibodies using the BenchMark XT automated stainer (Ventana Medical System Inc.; ref. 31). Afterward, on the bench, tumor slices were incubated with secondary antibodies as described above ("In vivo VEGF stimulation" section).…”