Abstract
Clear-cell renal cell carcinoma (ccRCC), the most common subtype of renal cancer, has a poor clinical outcome. A hallmark of ccRCC is genetic loss-of-function of VHL (von Hippel-Lindau) that leads to a highly vascularized tumor microenvironment. Although many ccRCC patients initially respond to antiangiogenic therapies, virtually all develop progressive, drug-refractory disease. Given the role of dysregulated expressions of cytoskeletal and cytoskeleton-regulatory proteins in tumor progression, we performed analyses of The Cancer Genome Atlas (TCGA) transcriptome data for different classes of actin-binding proteins to demonstrate that increased mRNA expression of profilin1 (Pfn1), Arp3, cofilin1, Ena/VASP, and CapZ, is an indicator of poor prognosis in ccRCC. Focusing further on Pfn1, we performed immunohistochemistry-based classification of Pfn1 staining in tissue microarrays, which indicated Pfn1 positivity in both tumor and stromal cells; however, the vast majority of ccRCC tumors tend to be Pfn1-positive selectively in stromal cells only. This finding is further supported by evidence for dramatic transcriptional up-regulation of Pfn1 in tumor-associated vascular endothelial cells in the clinical specimens of ccRCC. In vitro studies support the importance of Pfn1 in proliferation and migration of RCC cells and in soluble Pfn1's involvement in vascular endothelial cell tumor cell cross-talk. Furthermore, proof-of-concept studies demonstrate that treatment with a novel computationally designed Pfn1-actin interaction inhibitor identified herein reduces proliferation and migration of RCC cells in vitro and RCC tumor growth in vivo Based on these findings, we propose a potentiating role for Pfn1 in promoting tumor cell aggressiveness in the setting of ccRCC.
Highlights
The estimated incidence of and number of deaths from renal cell carcinoma (RCC) in the United States in 2019 are 73,280 and 14,770, respectively [1]
We found that expressions of a subset of actin-binding protein (ABP)-encoding genes represent indicators of better prognosis in clearcell RCC (ccRCC) (Table S1)
Pfn1 IHC of ccRCC tissue microarray (TMA) revealed three distinct patterns of Pfn1 expression: (i) negligible Pfn1 expression throughout the tumor (5.8% frequency), (ii) strong Pfn1 expression in stromal cells (VEC, lymphocytes) but negligible expression in tumor cells (64.5% frequency), and (iii) strong Pfn1 expression in both stromal and tumor cells (29.7% frequency). In the latter sample cohort, 71% of specimens exhibited a nuclear distribution of Pfn1 expression in tumor cells, with the remaining 29% of specimens characterized by nucleocytoplasmic staining of tumor cells. These findings suggest that the vast majority of ccRCC tumors display a pattern of strong Pfn1 expression selectively in stromal cells within the tumor microenvironment (TME); this is in accord with the general assessment of Minamida et al [14] in their qualitative evaluation of a limited number of ccRCC samples
Summary
The estimated incidence of and number of deaths from renal cell carcinoma (RCC) in the United States in 2019 are 73,280 and 14,770, respectively [1]. Proteomic studies further identified Pfn to be one of the candidate markers of late stage ccRCC [15, 16] In concordance with these findings, semiquantitative IHC studies performed on a larger cohort of patient samples (384 cases) subsequently established higher Pfn expression correlated with shorter overall survival (OS) and progression-free survival (PFS) of ccRCC patients [17]. Because those stratifications were based on percentages of Pfn1-immunoreactive regions on a semiquantitative evaluation scale, an accurate assessment of Pfn expression in different cell compartments in tumor versus normal adjacent regions of kidney in ccRCC patients is lacking in the literature Overall, these studies suggest Pfn1’s positive association with advanced disease features and adverse clinical outcomes in the setting of ccRCC. We demonstrate proof-of-concept for a novel Pfn1–actin interaction inhibitor identified to reduce RCC cell aggressiveness in vitro and tumor growth in vivo
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