Urologic Oncology: Seminars and Original Investigations
Original articleKIFC1 induces resistance to docetaxel and is associated with survival of patients with prostate cancer☆
Introduction
Prostate cancer (PCa) is the most common malignant tumor and the second most common cause of cancer-related deaths among men in the developed world [1]. Prostate-specific antigen (PSA) has contributed to the earlier detection of PCa. However, at least 10% of men with newly diagnosed PCa have locally advanced disease, and the prognosis of locally advanced or metastatic PCa remains unsatisfactory. Docetaxel has been an important treatment option for patients with metastatic castration-resistant prostate cancer (CRPC) [2]. However, nearly all patients with CRPC treated with docetaxel eventually become refractory. Therefore, there is an urgent need to understand drug resistance mechanisms in PCa.
During the past decade, cancer has been recognized as a stem cell disease [3]. Cancer stem cells (CSCs) have been described in numerous solid tumors, which are characterized by expression of specific cell surface markers such as aldehyde dehydrogenase 1, CD44, and CD133 [4], [5], [6]. CSCs are a small population among cancer cells and thought to be the origin of drug resistance. To characterize CSCs, a useful method is spheroid colony formation. These spheroid colonies have characteristics of the CSC phenotype, and it has been reported that prostate CSCs enriched from spheres are more resistant to chemotherapeutic drugs [7]. Therefore, analysis of drug resistance mechanisms requires characterization of CSCs. However, prostate CSCs have not been fully characterized.
Previously, we found higher expression of KIFC1 in spheroid body–forming cells than in parental cells of gastric cancer cell lines by microarray analysis [8]. The kinesin family member C1 (KIFC1) gene encodes KIFC1 protein (also known as HSET). KIFC1 is a C-type kinesin of the kinesin-14 family and assumed to be a minus end-directed motor protein [9]. Kinesins are a family of molecular motor proteins that play important roles in intracellular transport and cell division [10]. Because spheroid colonies have characteristics of the CSC phenotype, KIFC1 likely plays an important role in drug resistance. In fact, it has been reported that forced expression of KIFC1 inhibits docetaxel-mediated apoptosis [11]. Although up-regulation of KIFC1 has been reported in human cancers including glioblastoma, lung cancer, breast cancer, and colon cancer [10], the expression and biological significance of KIFC1 have not been investigated in PCa.
In the present study, we analyzed the expression and distribution of KIFC1 in human PCa by immunohistochemistry and examined the relationship between KIFC1 expression and clinicopathologic characteristics. We also analyzed the effect of inhibiting KIFC1 expression by RNA interference (RNAi) on the drug resistance.
Section snippets
Tissue samples
Using a retrospective study design, 200 primary tumors were collected from patients diagnosed with PCa, who were treated between 2003 and 2010 at Hiroshima University Hospital (Hiroshima, Japan). This study was approved by the Ethical Committee for Human Genome Research of Hiroshima University (Hiroshima, Japan).
For quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis, we used 18 PCa samples. All patients had undergone curative resection. Only patients without
Expression of KIFC1 in PCa
We first performed qRT-PCR analysis of KIFC1 in 14 types of normal tissue samples and 18 PCa tissue samples (Fig. 1A). Clinicopathologic characteristics of these 18 PCa samples were shown in Supplementary Table S1. Among the various normal tissue samples, abundant KIFC1 mRNA expression was found in normal prostate, lung, stomach, small intestine, colon, and spleen. Expression of KIFC1 in these normal tissue samples was highest in the colon. However, expression of KIFC1 in PCa tissue samples was
Discussion
In the present study, we analyzed the expression and biological function of KIFC1 in PCa. Immunohistochemical analysis of 157 clinically localized PCa cases demonstrated that PCa cells were positive for KIFC1, whereas weak or no staining of KIFC1 was observed in nonneoplastic prostate samples. We found associations between KIFC1 expression and the Gleason score and vascular invasion. Furthermore, KIFC1-positive PCa cases showed a high Ki-67-labeling index. Kaplan-Meier analysis showed poorer
Acknowledgments
We thank the Analysis Center of Life Science, Hiroshima University, for the use of their facilities.
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