Hyaluronic acid family in bladder cancer: potential prognostic biomarkers and therapeutic targets

Abstract

Background:Molecular markers of clinical outcome may aid in designing targeted treatments for bladder cancer. However, only a few bladder cancer biomarkers have been examined as therapeutic targets.Methods:Data from The Cancer Genome Atlas (TCGA) and bladder specimens were evaluated to determine the biomarker potential of the hyaluronic acid (HA) family of molecules – HA synthases, HA receptors and hyaluronidase. The therapeutic efficacy of 4-methylumbelliferone (4MU), a HA synthesis inhibitor, was evaluated in vitro and in xenograft models.Results:In clinical specimens and TCGA data sets, HA synthases and hyaluronidase-1 levels significantly predicted metastasis and poor survival. 4-Methylumbelliferone inhibited proliferation and motility/invasion and induced apoptosis in bladder cancer cells. Oral administration of 4MU both prevented and inhibited tumour growth, without dose-related toxicity. Effects of 4MU were mediated through the inhibition of CD44/RHAMM and phosphatidylinositol 3-kinase/AKT axis, and of epithelial–mesenchymal transition determinants. These were attenuated by HA, suggesting that 4MU targets oncogenic HA signalling. In tumour specimens and the TCGA data set, HA family expression correlated positively with β-catenin, Twist and Snail expression, but negatively with E-cadherin expression.Conclusions:This study demonstrates that the HA family can be exploited for developing a biomarker-driven, targeted treatment for bladder cancer, and 4MU, a non-toxic oral HA synthesis inhibitor, is one such candidate.

The investigation of hyaluronic acid and hyaluronidase‐1 levels as tumour marker in larynx cancer

“…In line with the oncogenic function of HYAL1 gene, increased hyaluronidase activity has been associated with high‐grade prostate cancer . In accordance with this report also increased HYAL1 transcript levels have been reported in bladder and ovarian cancer . HYAL1 expression has also been correlated with the grade, stage and multifocality of the tumours in bladder and colorectal cancers .…”

“…13 In accordance with this report also increased HYAL1 transcript levels have been reported in bladder and ovarian cancer. 10,14,15 HYAL1 expression has also been correlated with the grade, stage and multifocality of the tumours in bladder and colorectal cancers. 7,10 However, there is no study in the literature investigating the HYAL1 gene in larynx cancer.…”

Bioinformatics Analysis to Screen the Key Prognostic Genes in Tumor Microenvironment of Bladder Cancer

“…One of the basic challenges in cancer is to detect the regulators of gene expression changes in tumorigenesis and the correlation between that and prognosis. e different intracellular signal transduction pathways of low-grade and high-grade tumor heterogeneity in tumor progression and postoperative recurrence are some of the unique characteristics of bladder cancer that contribute to the challenges of evaluating the tumor prognosis [46,47]. e Cancer Genome Atlas (TCGA) and other large-scale collaborative initiatives collect the comprehensive molecular characterization of multiple cancer types and patients' clinical data and thus provide opportunities for the studies of the genomic and molecular characterization of BLCA [48,49].…”

Identification and Prognostic Analysis of Hub Genes in Bladder Cancer

“…Previous studies showed that HMMR involved in oncogenic properties several mechanisms in multiple cancers, such as in uencing mitotic spindle assembly, regulating cell signaling pathways, and modulating the expression of growth factor receptor [29,33]. HMMR has also been found over expressed in gastric cancer 33 , glioblastoma 34 ,head and neck carcinomas 35 .The increased expression of HMMR directly leads to an increase in the metastatic potential of many types of tumors, including prostate cancer 36 , breast cancer 37 , colorectal cancer 38 ,and bladder cancer 39 . Available evidence showed that HMMR is considered to be an important downstream regulator of HA, which can lead to the rapid growth of bladder cancer cells 40 .One recent study showed that inhibition of HMMR expression in vitro can reduce the proliferation of bladder cancer cells and inhibit the growth of xenograft tumors in vivo 41 .These results suggest that HMMR mediates an important signaling pathway for bladder cancer cell growth and proliferation.…”