Intrinsic or acquired resistance to cisplatin (CDDP) is a problem for its use in cancer chemotherapy. This resistance has been reported to correlate with expression of the human copper transporter 1 and two copper export pumps, ATP7A and ATP7B. In the current study, we investigated the correlation between the expression of these transporters and sensitivity to CDDP using four cell lines derived from each of high invasive oral squamous cell carcinoma (OSCC) and low invasive OSCC. We found that the amount of CDDP accumulated in high invasive OSCC cell lines (Yamamoto-Kohama criteria: grade 4C and 4D) with strong intrinsic tolerance was lower than in low invasive OSCC cell lines (grade 3) with weak intrinsic tolerance. Additionally, overexpression of ATP7B mRNA in cell lines derived from high invasive OSCC conferred low sensitivity to CDDP. Furthermore, the accumulation and sensitivity of CDDP was higher in HOC313 cells transfected with the ATP7B siRNA than in cells transfected with the nonsense siRNA. These results suggest that the overexpression of ATP7B results in the export of and, therefore, resistance to CDDP. Furthermore, ATP7B may be a key determinant of the intrinsic resistance to CDDP.

The aim of this study was to examine the effects of fibroblast growth factor-2 (FGF-2) on cancer cell invasion and on fibroblast proliferation in an in vitro model of invasion. Three kinds of human oral squamous cell carcinoma cell lines with different invasive activity were used: OSC-20, OSC-19 (lower invasive type), and HOC313 (higher invasive type). FGF-2 and its high-affinity receptors FGFR-1 and FGFR-2 were detected by western blotting. The expression of FGF-2 and FGFRs mRNA was examined in cultured human oral squamous cell carcinoma cells by reverse transcriptase polymerase chain reaction (RT-PCR). Furthermore, recombinant human FGF-2 (rhFGF-2) was reacted with each cell line, and the invasion rate was determined by invasion assay. We also observed the behavior of cancer cell invasion in the collagen gel invasion model in the presence or absence of FGF-2-neutralizing antibody (anti-FGF-2). HOC313 cells showed higher expression of FGF-2 than OSC-20 and OSC-19 cells. The addition of rhFGF-2 promoted not only the proliferation of fibroblasts, but also the invasion of all cancer cell lines. In contrast, the addition of anti-FGF-2 completely inhibited the invasion of OSC-20 and OSC-19 cells. These results suggest that a higher invasiveness of squamous carcinoma cells is associated with higher production of FGF-2, which acts in an autocrine fashion to promote cancer cell invasion, and in a paracrine fashion to promote fibroblast proliferation.