Abstract
An established inverse clinical correlation between serum adiponectin levels and renal cell carcinoma (RCC) aggressiveness exists. We have recently demonstrated that adiponectin suppresses clear cell RCC (ccRCC) progression through interaction with its receptor, adiponectin receptor 1 (AdipoR1). ERp46 has been shown to inhibit adiponectin signaling via interaction with AdipoR1 in HeLa cells. However, the expression of ERp46 in RCC has not been described thus far. The objectives of this study were to investigate ERp46 in RCC, its expression, its effects on RCC growth in a mouse model and whether it interacts with AdipoR1. We demonstrated a higher ERp46/AdipoR1 expression ratio in metastatic compared to non-metastatic ccRCC, as determined by immunohistochemistry of tissue microarrays and subsequent image analysis. When ERp46 was stably knocked down using shRNA or overexpressed in murine RCC RAG cells, RCC growth after subcutaneous injection in BALB/c nude mice was inhibited and accelerated, respectively. In vitro analysis to determine the molecular interaction between AdipoR1 and ERp46 included co-immunoprecipitation using human ccRCC 786-O cells and a bacterial adenylate cyclase-based two hybrid system and demonstrated no sustained AdipoR1-ERp46 interaction. This is the first report to suggest a role for ERp46 as a potential therapeutic target in RCC given its expression profile in human RCC samples and its effect on in vivo RCC growth. Since a stable interaction with AdipoR1 could not be established, we suggest that the tumorigenic properties of ERp46 in RCC cells are not related to an inhibitory modulation of AdipoR1.
Highlights
Altered levels of fat tissue-derived hormones in obesity, an established risk factor for renal cell carcinoma (RCC) [1], can potentiate the growth of different cancers
We demonstrate a significantly higher ERp46/adiponectin receptor 1 (AdipoR1) expression ratio in metastatic clear cell RCC (ccRCC) compared to non-metastatic ccRCC and show that increased expression of ERp46 promotes RCC growth in vivo
Using ERp46-immunohistochemistry on tissue microarrays containing ccRCC samples of different stages and corresponding metastatic and normal renal specimens, we show the presence of ERp46 protein in specimens from ccRCC (Figure 1c) and in normal renal tissue (Figure 1ab)
Summary
Altered levels of fat tissue-derived hormones in obesity, an established risk factor for renal cell carcinoma (RCC) [1], can potentiate the growth of different cancers. Maximizing tumor suppressive signaling may be achieved by targeting its negative regulators [8,9] It has recently been demonstrated in Chinese hamster ovary cells, that endoplasmic reticulum (ER) protein ERp46, a member of the protein disulphide isomerase (PDI) family of oxidoreductases [10], binds to recombinant human Flag-tagged AdipoR1 and that knockdown of ERp46 leads to an increase in activation of AMPK in HeLa cells [11]. Whether this interaction occurs under native conditions and is responsible for enhancing cancer cell proliferation remains elusive. The tumorigenic properties of ERp46 in RCC cells are not likely related to an inhibitory modulation of adiponectin’s tumor-suppressive signaling, as an interaction with AdipoR1 could not be established
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