The ECM Modulator ITIH5 Affects Cell Adhesion, Motility and Chemotherapeutic Response of Basal/Squamous-Like (BASQ) Bladder Cancer Cells

Abstract

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.

ITIH5-Derived Polypeptides Covering the VIT Domain Suppress the Growth of Human Cancer Cells In Vitro

“…Recently, Huth et al proposed the formation of HA cable-like structures by ITIH5 in the skin [13]. Additionally, the prognostic significance of ITIH5 has been demonstrated in bladder cancer in close association with abundant CD44 expression; matching this observation, SCaBER bladder cancer cells abundantly expressing CD44 could be sensitized to cisplatin treatment after forced ITIH5 expression in vitro [18].…”

Urine inter‐alpha‐trypsin inhibitor family‐related proteins may serve as biomarkers for disease activity of lupus

“…ITIH5 is known as a tumor suppressor gene for various cancers (breast cancer, bladder cancer, pancreatic cancer, etc.). 45 , 46 , 47 In recent years, some studies have found that ITIH5 is the major ITIH family member expressed in human skin and is a natural stabilizer of hyaluronic acid. 48 The complex formed by ITIH5 and HA stabilized HA and promoted the formation of ECM structure, meanwhile regulating inflammation.…”

“…ITIH5 is known as a tumor suppressor gene for various cancers (breast cancer, bladder cancer, pancreatic cancer, etc.) 45–47 . In recent years, some studies have found that ITIH5 is the major ITIH family member expressed in human skin and is a natural stabilizer of hyaluronic acid 48 .…”

ITIH5, as a predictor of prognosis and immunotherapy response for P53-like bladder cancer, is related to cell proliferation and invasion

“…Rose et al showed that the prognostic value of ITIH5 expression in basal cell type MIBC was closely related to the expression of CD44. 28 Overexpression of ITIH5 could inhibit the growth and migration of BLCA cells in the case of high expression of CD44. However, the role of ITIH5 in p53-like BLCA remains to be studied.…”