Negative regulation between the expression levels of receptor for hyaluronic acid‑mediated motility and hyaluronan leads to cell migration in pancreatic cancer

Abstract

Receptor for hyaluronic acid (HA)-mediated motility (RHAMM) expression is upregulated in pancreatic ductal adenocarcinoma (PDAC). In the present study, small interfering RNA knockdown was used to investigate the regulatory mechanism and function of RHAMM in PDAC cells. Reverse transcription-quantitative PCR was used to measure the mRNA expression levels of RHAMM, hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1, HYAL2 and HYAL3) in eight PDAC cell lines. Cell migration was assessed using a Transwell assay, while HA concentration was measured using an ELISA. The results revealed that RHAMM-knockdown significantly increased migration in two PDAC cell lines, significantly decreased migration in one cell line and did not affect migration in the other cell lines, and was positively associated with changes in HA production. There was a linear negative correlation between RHAMM mRNA expression and HA concentration in PDAC cells and tissues. The negative correlation between RHAMM mRNA expression and HA concentration was demonstrated in other models, including SUIT2 cells treated with an HA inhibitor or stimulator and a system involving co-culture of SUIT2 cells and stromal fibroblasts. The present findings demonstrated a negative correlation between RHAMM mRNA expression and HA production in a subset of PDAC cell lines. The efficacy of a therapeutic strategy targeting RHAMM should be carefully evaluated in future studies.

CD44 and RHAMM Are Microenvironmental Sensors with Dual Metastasis Promoter and Suppressor Functions

“…[ 70 ] This result was initially attributed to the enhanced expression of residual exons remaining from the knockout design that were translated into an N‐terminal protein fragment expressed in testes and pancreatic tumors and postulated but not directly demonstrated, to be oncogenic. [ 72 ] However, more complete RHAMM knockdown significantly increases rather than decreases functions relevant to tumor progression such as migration of some pancreatic ductal adenocarcinoma cell lines, [ 90 ] which supports a role for RHAMM as a cell context‐dependent tumor suppressor. This possibility is strengthened by evidence that crossing the Rhamm −/− mouse used in pancreatic cancer models to an MMTV‐PyMT mouse model of breast tumor susceptibility increases lung metastases although primary tumor initiation and growth are unaffected.…”

Functional organization of extracellular hyaluronan, CD44, and RHAMM

“…HA rescues the motility of hyaluronidase-treated cells but not in the presence of RHAMM antibodies. 249 It is notable that RHAMM does not always function to promote celll motility 7,255,256 and this may result from its intracellular sequestration and/or its association with partner proteins such as CD44. Here, we review the biology of extracellular RHAMM from the perspective of its extracellular association with HA and CD44.…”

Clinically Relevant Biology of Hyaluronic Acid in the Desmoplastic Stroma of Pancreatic Ductal Adenocarcinoma

“…38 To understand the mechanism of action of HMMR, a study attempted to knockdown HMMR in 8 PDAC cell lines to evaluate the effects on HA quantity and expression of HAS1-3 and HYAL1-3. 39 In each cell line, the outcome was different, possibly due to varying degrees of knockdown. Among cell lines that demonstrated significant levels of knockdown, 2 of them (SUIT-2, PANC-1) showed increased invasiveness in combination with increased HAS2 mRNA and HA secretion into cell culture media.…”

“…To understand the mechanism of action of HMMR, a study attempted to knockdown HMMR in 8 PDAC cell lines to evaluate the effects on HA quantity and expression of HAS1–3 and HYAL1–3 39 . In each cell line, the outcome was different, possibly due to varying degrees of knockdown.…”