Thesis or Dissertation Significant association of caveolin-1 and caveolin-2 with prostate cancer progression

Sugie, Satoru  ,  Mukai, Shoichiro  ,  Yamasaki, Koji  ,  Kamibeppu, Toyoharu  ,  Tukino, Hiromasa  ,  Kamoto, Toshiyuki

Background/Aim: Up-regulation of caveolin (CAV)-1 is associated with aggressive prostate cancer. Recently, it has been inferred that CAV2, a co-factor sub-type of CAV1, cross-talks with CAV1 and promotes tumor growth. We previously reported that plasma CAV1 levels are elevated in patients with castration-resistant prostate cancer (CRPC), but not in hormone-sensitive prostate cancer (non-CRPC), implying that CAV1 may be a therapeutic target for CRPC. However, a correlation of CAV1 and CAV2 expression in PC has not yet been reported. Herein, we analyzed associations between PC progression and plasma CAV1 and -2 in Japanese men, and expression of CAV1 and -2 in PC3 (CRPC) and LNCaP (non-CRPC) cell lines. Materials and Methods: We investigated plasma samples from 36 patients with CRPC and 22 with non-CRPC. We used enzyme-linked immunosorbent assay (ELISA) to determine plasma levels of CAV1 and -2, and examined correlations with clinicopathological characteristics such as Gleason grade and clinical T stage. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate CAV1 and CAV2 mRNA in PC cell lines. We also introduced CAV1- and CAV2-specific small interfering (siRNA) into PC3 cells to knock-down (KD) both molecules, and examined its influence on the expression of these genes between PC3 CAV1 and -2 KD cells and control cells. Results: Plasma CAV1 and -2 levels in patients with CRPC were significantly higher than in those with non-CRPC (CAV1, p=0.003; CAV2, p<0.001). Plasma levels of CAV1 and -2 were significantly correlated (p<0.001). However, we did not find any significant relationship between CAV1 or CAV2 expression and clinicopathological factors. ELISA and real-time qRT-PCR showed that both proteins and mRNAs in PC3 cells were significantly over-expressed compared to LNCaP cells (p<0.001). In PC3 CAV1 KD cells, expression of CAV2 was suppressed and confirmed the linkage of CAV2 KD and suppression of CAV1 expression. Conclusion: There was a significant correlation between plasma CAV-1 and -2 levels and progression of PC. CAV1 and -2 were highly expressed in the PC3 compared to the LNCaP cell line. Our findings support the potential of these molecules as therapeutic targets for CRPC. Prostate cancer (PC) is the sixth leading cause of cancerrelated death among Japanese men (1), usually from metastatic disease. Understanding the mechanisms that underlie the progression of PC will facilitate the development of biomarkers and novel therapeutic strategies to control this devastating malignancy. Caveolin (CAV)-1 and CAV2, encoded by their respective genes, are major structural components of the caveolae that are co-expressed and form a hetero-oligomeric complex in many cell types, with particularly high levels in adipocytes (2). CAV1 expression is increased in cancer of the prostate (3-5), pancreas (6, 7), colon (8, 9), breast (10) and esophagus (11, 12), thus suggesting it plays a positive role in tumor progression. Paradoxically, CAV1 expression is decreased in lung (13), colon (14, 15), ovarian (16), breast (17, 18) and thyroid (19) cancer. These data imply that CAV1 has multiple activities in cancer depending on its interaction with other signaling molecules and the specific cell type or tissue in which it is expressed. Therefore, whether CAV1 promotes or suppresses tumor progression remains controversial. CAV2 has similar distribution and tissue expression to CAV1, and is also an accessory protein that functions in conjunction with CAV1. CAV2 expression is increased in breast cancer (10), whereas is reduced in lung (13), breast (10, 17) and thyroid cancer (19). However, the clinical significance of CAV2 has been less extensively studied than that of CAV1. Therefore, in the present study, we examined plasma CAV1 and -2 levels and analyzed them with clinical data by enzyme-linked immunosorbent assay (ELISA). In addition, the expression of CAV1 and -2 was investigated using PC cell lines PC3 (castration-resistant PC; CRPC) and LNCaP (hormone-sensitive; non-CRPC) by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and ELISA to clarify the significance of CAV1 and -2.

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