Institute of Pathology, University Hospital RWTH Aachen University, 52074 Aachen, Germany.
Institute of Biological Information Processing 2 (IBI-2), Mechanobiology, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany.
Cells. 2021 Apr 28;10(5):1038. doi: 10.3390/cells10051038.
This study aims at characterizing the role of the putative tumor suppressor ITIH5 in basal-type bladder cancers (BLCA). By sub-classifying TCGA BLCA data, we revealed predominant loss of ITIH5 expression in the basal/squamous-like (BASQ) subtype. ITIH5 expression inversely correlated with basal-type makers such as KRT6A and CD44. Interestingly, Kaplan-Meier analyses showed longer recurrence-free survival in combination with strong CD44 expression, which is thought to mediate ITIH-hyaluronan (HA) binding functions. In vitro, stable ITIH5 overexpression in two basal-type BLCA cell lines showing differential CD44 expression levels, i.e., with (SCaBER) and without squamous features (HT1376), demonstrated clear inhibition of cell and colony growth of BASQ-type SCaBER cells. ITIH5 further enhanced HA-associated cell-matrix attachment, indicated by altered size and number of focal adhesion sites resulting in reduced cell migration capacities. Transcriptomic analyses revealed enrichment of pathways and processes involved in ECM organization, differentiation and cell signaling. Finally, we provide evidence that ITIH5 increase sensitivity of SCaBER cells to chemotherapeutical agents (cisplatin and gemcitabine), whereas responsiveness of HT1376 cells was not affected by ITIH5 expression. Thus, we gain further insights into the putative role of ITIH5 as tumor suppressor highlighting an impact on drug response potentially via the HA-CD44 axis in BASQ-type BLCA.
本研究旨在探讨假定的肿瘤抑制因子 ITIH5 在基底样膀胱癌（BLCA）中的作用。通过对 TCGA BLCA 数据进行亚分类，我们揭示了 ITIH5 在基底/鳞状样（BASQ）亚型中的表达明显缺失。ITIH5 的表达与基底型标志物如 KRT6A 和 CD44 呈负相关。有趣的是，Kaplan-Meier 分析显示，与 CD44 表达较强的患者相比，联合表达 ITIH5 具有更长的无复发生存期，这被认为介导了 ITIH-透明质酸（HA）结合功能。在体外，在具有不同 CD44 表达水平的两种基底样 BLCA 细胞系（即具有（SCaBER）和无鳞状特征（HT1376））中稳定过表达 ITIH5，清楚地抑制了 BASQ 型 SCaBER 细胞的细胞和集落生长。ITIH5 进一步增强了 HA 相关的细胞-基质附着，表现为焦点附着部位的大小和数量发生改变，从而降低了细胞迁移能力。转录组分析显示，涉及细胞外基质组织、分化和细胞信号转导的途径和过程明显富集。最后，我们提供了证据表明 ITIH5 增加了 SCaBER 细胞对化疗药物（顺铂和吉西他滨）的敏感性，而 HT1376 细胞对 ITIH5 表达的反应不受影响。因此，我们进一步深入了解了 ITIH5 作为肿瘤抑制因子的潜在作用，强调了其对 BASQ 型 BLCA 中药物反应的潜在影响，可能通过 HA-CD44 轴。
