Abstract
Previous studies indicated the T cells, one of the most common types of immune cells existing in the microenvironment of renal cell carcinoma (RCC), may influence the progression of RCC. The potential linkage of T cells and the estrogen receptor beta (ERβ), a key player to impact RCC progression, however, remains unclear. Our results demonstrate that RCC cells can recruit more T cells than non-malignant kidney cells. Using an in vitro matrigel invasion system, we found infiltrating T cells could promote RCC cells invasion via increasing ERβ expression and transcriptional activity. Mechanism dissection suggested that co-culturing T cells with RCC cells released more T cell attraction factors, including IFN-γ, CCL3 and CCL5, suggesting a positive regulatory feed-back mechanism. Meanwhile, infiltrating T cells may also promote RCC cell invasion via increased ERβ and decreased DAB2IP expressions, and knocking down DAB2IP can then reverse the T cells-promoted RCC cell invasion. Together, our results suggest that infiltrating T cells may promote RCC cell invasion via increasing the RCC cell ERβ expression to inhibit the tumor suppressor DAB2IP signals. Further mechanism dissection showed that co-culturing T cells with RCC cells could produce more IGF-1 and FGF-7, which may enhance the ERβ transcriptional activity. The newly identified relationship between infiltrating T cells/ERβ/DAB2IP signals may provide a novel therapeutic target in the development of agents against RCC.
Highlights
Renal cell carcinoma (RCC) is the most common kidney cancer and third leading cause of death among urological tumors [1]
To examine the potential impacts of CD4+ T cells in the renal cell carcinoma (RCC) development, we first tested whether RCC cells, compared to non-malignant kidney cells, could better attract the CD4+ T cells, HH, which were used in this study
The T cells were seeded in the upper transwells and 2 different RCC cells 786-O and A498, or nonmalignant kidney HKC-2 cells were seeded in the bottom wells
Summary
Renal cell carcinoma (RCC) is the most common kidney cancer and third leading cause of death among urological tumors [1]. There are four subtypes of RCC and clear cell tumor subtype is the most common type, accounting for 80% of all RCCs [2]. The inactivating mutation in the von Hippel–Lindau (VHL) gene, a tumor suppressor, is frequently observed in clear cell RCC [3]. RCC patients can develop resistance to chemotherapy and radiation therapy, kidney resection is considered to be the effective treatment for patients with clinically localized RCC. The postoperative recurrence in RCC patients who undergo curative nephrectomy is only around 20% to 40% and rarely curable [4]. There is a clear need to improve treatment options for metastatic RCC
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