Authors' Affiliations: Fisiopatología Renal, CIBBIM; Statistics and Bioinformatics Unit (UEB), Vall d'Hebron Institute of Research; Servicio de Urología, Hospital Vall d'Hebron; Servicio de Anatomía Patológica, Hospital Vall d'Hebrón; Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica, Facultat de Biociències; Departament de Bioquimica i Biologia Molecular, Unitat de Bioquímica de Medicina, Universitat Autònoma de Barcelona, Bellaterra; and Instituto Reina Sofía de Investigación Nefrológica, Fundación Renal Íñigo Álvarez de Toledo, Spain.
Cancer Res. 2014 Mar 1;74(5):1416-28. doi: 10.1158/0008-5472.CAN-13-1671. Epub 2014 Jan 3.
Renal cell carcinoma (RCC), the third most prevalent urological cancer, claims more than 100,000 lives/year worldwide. The clear cell variant (ccRCC) is the most common and aggressive subtype of this disease. While commonly asymptomatic, more than 30% of ccRCC are diagnosed when already metastatic, resulting in a 95% mortality rate. Notably, nearly one-third of organ-confined cancers treated by nephrectomy develop metastasis during follow-up care. At present, diagnostic and prognostic biomarkers to screen, diagnose, and monitor renal cancers are clearly needed. The gene encoding the cell surface molecule HAVCR1/KIM-1 is a suggested susceptibility gene for ccRCC and ectodomain shedding of this molecule may be a predictive biomarker of tumor progression. Microarray analysis of 769-P ccRCC-derived cells where HAVCR/KIM-1 levels have been upregulated or silenced revealed relevant HAVCR/KIM-1-related targets, some of which were further analyzed in a cohort of 98 ccRCC patients with 100 month follow-up. We found that HAVCR/KIM-1 activates the IL-6/STAT-3/HIF-1A axis in ccRCC-derived cell lines, which depends on HAVCR/KIM-1 shedding. Moreover, we found that pSTAT-3 S727 levels represented an independent prognostic factor for ccRCC patients. Our results suggest that HAVCR/KIM-1 upregulation in tumors might represent a novel mechanism to activate tumor growth and angiogenesis and that pSTAT-3 S727 is an independent prognostic factor for ccRCC.
肾细胞癌（RCC）是第三大常见的泌尿系统癌症，全球每年导致超过 10 万人死亡。透明细胞变体（ccRCC）是这种疾病最常见和最具侵袭性的亚型。虽然通常无症状，但超过 30%的 ccRCC 在已经转移时被诊断出来，导致 95%的死亡率。值得注意的是，近三分之一的通过肾切除术治疗的局限性癌症在随访期间发展为转移。目前，迫切需要用于筛选、诊断和监测肾肿瘤的诊断和预后生物标志物。编码细胞表面分子 HAVCR1/KIM-1 的基因是 ccRCC 的一个候选易感基因，并且该分子的外显子脱落可能是肿瘤进展的预测性生物标志物。对 HAVCR/KIM-1 水平上调或沉默的 769-P ccRCC 衍生细胞的微阵列分析揭示了相关的 HAVCR/KIM-1 相关靶标，其中一些靶标在 98 例 ccRCC 患者的队列中进行了进一步分析，随访时间为 100 个月。我们发现 HAVCR/KIM-1 在 ccRCC 衍生细胞系中激活了 IL-6/STAT-3/HIF-1A 轴，这取决于 HAVCR/KIM-1 的脱落。此外，我们发现 pSTAT-3 S727 水平是 ccRCC 患者的独立预后因素。我们的结果表明，肿瘤中 HAVCR/KIM-1 的上调可能代表一种新的机制来激活肿瘤生长和血管生成，并且 pSTAT-3 S727 是 ccRCC 的独立预后因素。
