Abstract
Metastasis is present in approximately 30% of patients diagnosed with renal cell carcinoma (RCC) and is associated with a 5-year survival rate of < 15%. Kidney injury molecule 1 (KIM-1), encoded by the HAVCR1 gene, is a proximal tubule cell-surface glycoprotein and a biomarker for early detection of RCC, but its pathophysiological significance in RCC remains unclear. We generated human and murine RCC cell lines either expressing or lacking KIM-1, respectively, and compared their growth and metastatic properties using validated methods. Surprisingly, KIM-1 expression had no effect on cell proliferation or subcutaneous tumour growth in immune deficient (Rag1−/−) Balb/c mice, but inhibited cell invasion and formation of lung metastasis in the same model. Further, we show that the inhibitory effect of KIM-1 on metastases was observed in both immune deficient and immune competent mice. Transcriptomic profiling identified the mRNA for the pro-metastatic GTPase, Rab27b, to be downregulated significantly in KIM-1 expressing human and murine RCC cells. Finally, analysis of The Cancer Genome Atlas (TCGA) data revealed that elevated HAVCR1 mRNA expression in the two most common types of RCC, clear cell and papillary RCC, tumours correlated with significantly improved overall patient survival. Our findings reveal a novel role for KIM-1 in inhibiting metastasis of RCC and suggests that tumour-associated KIM-1 expression may be a favourable prognostic factor.
Highlights
Metastasis is present in approximately 30% of patients diagnosed with renal cell carcinoma (RCC) and is associated with a 5-year survival rate of < 15%
We previously demonstrated that Kidney injury molecule 1 (KIM-1) expression on injured renal proximal tubular cells inhibits Gα12 activation downstream signalling via RhoA—a small GTPase implicated in invasion and m etastasis[18]
We explored the role of tumour-associated KIM-1 in RCC using human and murine models
Summary
Metastasis is present in approximately 30% of patients diagnosed with renal cell carcinoma (RCC) and is associated with a 5-year survival rate of < 15%. KIM-1 expression by RCC cells is associated with increased levels of TGF-β, which has been shown to promote metastatic invasion in independent studies[16,17]. To study whether KIM-1-mediated inhibition of metastasis is dependent on adaptive immunity, Renca or 786-O cells were instead injected into the tail veins of immunedeficient BALB/c (Rag1−/−) mice in the same manner as described above.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call