Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, ON, Canada.
Sci Rep. 2021 Jun 4;11(1):11840. doi: 10.1038/s41598-021-90919-8.
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.
转移发生在大约 30%的被诊断患有肾细胞癌（RCC）的患者中，其 5 年生存率<15%。肾损伤分子 1（KIM-1）由 HAVCR1 基因编码，是近端肾小管细胞表面糖蛋白，是 RCC 早期检测的生物标志物，但它在 RCC 中的病理生理意义尚不清楚。我们分别生成了表达或缺乏 KIM-1 的人源和鼠源 RCC 细胞系，并使用经过验证的方法比较了它们的生长和转移特性。令人惊讶的是，KIM-1 的表达对免疫缺陷（Rag1）Balb/c 小鼠中的细胞增殖或皮下肿瘤生长没有影响，但抑制了同一模型中的细胞侵袭和肺转移形成。此外，我们表明 KIM-1 对转移的抑制作用在免疫缺陷和免疫功能正常的小鼠中均观察到。转录组分析确定，表达 KIM-1 的人源和鼠源 RCC 细胞中促转移 GTPase Rab27b 的 mRNA 显著下调。最后，对癌症基因组图谱（TCGA）数据的分析表明，两种最常见的 RCC（透明细胞和乳头状 RCC）中 HAVCR1 mRNA 表达的升高与患者总生存率的显著提高相关。我们的发现揭示了 KIM-1 在抑制 RCC 转移中的新作用，并表明肿瘤相关的 KIM-1 表达可能是一个有利的预后因素。
