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

Cells. 2021 Apr 28;10(5):1038. doi: 10.3390/cells10051038.

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.

Keywords: BASQ subtype; CD44; ITIH5; bladder cancer; chemosensitizer; hyaluronan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Cell Adhesion
  • Cell Proliferation
  • Cisplatin / administration & dosage
  • DNA Methylation
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Neoplasms, Basal Cell / drug therapy
  • Neoplasms, Basal Cell / genetics
  • Neoplasms, Basal Cell / metabolism
  • Neoplasms, Basal Cell / pathology*
  • Prognosis
  • Promoter Regions, Genetic
  • Proteinase Inhibitory Proteins, Secretory / genetics
  • Proteinase Inhibitory Proteins, Secretory / metabolism*
  • Retrospective Studies
  • Survival Rate
  • Tumor Cells, Cultured
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology*

Substances

  • Biomarkers, Tumor
  • ITIH5 protein, human
  • Proteinase Inhibitory Proteins, Secretory
  • Deoxycytidine
  • gemcitabine
  • Cisplatin