Expression Of Hyaluronan-mediated Motility Receptor Research Articles

Abstract 1157: Single-cell transcriptmoics identifies rhamm positive proliferative cells within human colorectal cancer stem cells

Abstract Cancer stem cells (CSCs) can be prospectively isolated based on specific surface marker such as CD44, CD133, LGR5, and CD166, in human colorectal cancer. However, the employment of these CSCs' markers are still insufficient to prospectively isolate the colorectal CSCs. To overcome the cellular heterogeneity of previously reported CSCs fraction, we performed single-cell mRNA sequencing (scRNAseq) of 72 cells within organoid. By conducting scRNAseq, we identified CSCs-like sub-population with high expression of MKI67 and Cyclin families, which was generally expressed in proliferative state of the cells within the organoid. Remarkably, high expression of hyaluronan-mediated motility receptor (HMMR) encoding cell membranous and cytoplasmic molecule, receptor for hyaluronan mediated motility (RHAMM), which was reported to associate with CD44 in hyaluronan binding, was observed in the CSCs-like cells. Prospective isolation of RHAMM+ CD44+ cells, that were sub-population of conventional CSCs fraction, revealed higher organoid- and tumor-forming abilities. Furthermore, comprehensive gene expression analysis also demonstrated the proliferative gene expression within RHAMM+ CD44+ cells. Here, we report RHAMM+ proliferative cells that sub-fraction the conventional CSCs population. <!–EndFragment–> Citation Format: Michitaka Nakano, Kikushige Yoshikane, Kohta Miyawaki, Shinichi Mizuno, Kyoko Yamaguchi, Takuji Yamauchi, Hiroshi Ariyama, Hitoshi Kusaba, Masafumi Nakamura, Takahiro Maeda, Eishi Baba, Koichi Akashi. Single-cell transcriptmoics identifies rhamm positive proliferative cells within human colorectal cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1157.

Hyaluronan‐mediated motility receptor confers resistance to chemotherapy via TGFβ/Smad2‐induced epithelial‐mesenchymal transition in gastric cancer

Chemotherapy is one of the vital treatments for gastric cancer (GC) patients, especially those suffering advanced stages. Chemoresistance results in tumor relapse, leading to poor prognosis in GC patients; thus, identifying key regulators in this process might provide novel clues for GC therapy. Herein, we identify hyaluronan-mediated motility receptor (HMMR) as a key regulator of chemoresistance in GC. HMMR was found to be substantially up-regulated in 5-fluorouracil (5-Fu)-resistant GC biopsies and cell lines. High expression of HMMR significantly correlates with tumor relapse and predicts poorer prognosis in GC patients. Moreover, we observed that HMMR induced epithelial-mesenchymal transition and increased the cancer stem cell properties of GC, thus rendering resistance to chemotherapy. Importantly, silencing of HMMR effectively increased the susceptibility to 5-Fu therapy both in vitro and in vivo. Furthermore, we demonstrated that HMMR activates the TGF-β/Smad2 signaling pathway, which was required for the HMMR-mediated oncogenic effects and exhibited significant clinical relevance with HMMR expression. These findings reveal a critical role for HMMR in the chemoresistance of GC and suggest that HMMR might be a potential prognostic marker or therapeutic target against the disease.-Zhang, H., Ren, L., Ding, Y., Li, F., Chen, X., Ouyang, Y., Zhang, Y., Zhang, D. Hyaluronan-mediated motility receptor confers resistance to chemotherapy via TGFβ/Smad2-induced epithelial-mesenchymal transition in gastric cancer.

PS02.200: A COMPREHENSIVE SCREENING OF THE FRA-1 REGULATORY GENES IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background The expression of Fos-related antigen 1 (Fra-1) affects tumor progression, migration and invasion. We previously reported that a high Fra-1 expression level is associated with lymph node metastasis and a poor prognosis in patients with esophageal squamous cell carcinoma (ESCC). In this study, we identified the genes regulated by Fra-1 in ESCC. Methods We constructed Fra-1 knockdown models via the transfection of small interfering RNA (siRNA) into ESCC cell lines (TE10, TE11). The expression levels of the genes in the knockdown models were analyzed using a microarray experiment and Biobase Upstream Analysis (Cytoline Solutions, Tokyo, Japan), and candidate genes regulated by Fra-1 in the ESCC cell lines were detected. The actual connection of Fra-1 to the promoter region was identified in a ChIP-PCR experiment. The expression levels of the candidate genes regulated by Fra-1 in the primary tumors of surgical specimens obtained from ESCC patients (n = 135) were compared to those observed in normal tissues using real-time PCR and immunohistochemical staining, and the clinicopathological features were analyzed. Results The results of the Biobase Upstream Analysis and ChIP-PCR showed high mobility group protein 1 (HMGA1) and hyaluronan mediated motility receptor (HMMR) to be significant genes regulated by Fra-1. The expression levels of both HMGA1 and HMMR were found to closely correlate with the Fra-1 expression in the clinical specimens. The patients with a positive HMGA1 expression had a poorer prognosis than those with a negative expression (P = 0.017) and the patients with positive HMMR expression also had a poorer prognosis (P = 0.018). Moreover, a multivariate analysis demonstrated a positive HMGA1 expression to be a significant independent prognostic factor in the ESCC patients. Conclusion HMGA1 and HMMR are regulated by Fra-1 in the setting of ESCC and the HMGA1 expression is significantly associated with a poor prognosis in ESCC patients. Downregulating the HMGA1 and HMMR expression may become a practical treatment strategy against ESCC in the future. Disclosure All authors have declared no conflicts of interest.

HMMR antisense RNA 1, a novel long noncoding RNA, regulates the progression of basal-like breast cancer cells.

Recently, accumulating evidence has suggested that long noncoding RNAs (lncRNAs) play crucial roles in carcinogenesis and cancer progression. Hyaluronan-mediated motility receptor (HMMR) is an essential cancer-related gene in basal-like breast cancer (BLBC). In our study, HMMR antisense RNA 1 (HMMR-AS1) was analyzed in BLBC patients through polymerase chain reaction analysis. Here, we found that the expression of HMMR was positively correlated with HMMR-AS1 (RP11-80G.1). When HMMR-AS1 (RP11-80G.1) was knocked down, the expression of HMMR markedly reduced. Furthermore, in MDA-MB-231 and MDA-MB-468 breast cancer cells, the proliferation and migration abilities were remarkably suppressed via knocking down HMMR-AS1 (RP11-80G.1) in vitro. The results showed that lncRNA HMMR-AS1 (RP11-80G.1) influenced the progression of BLBCs through regulating HMMR, suggesting that HMMR-AS1 (RP11-80G.1) could be regarded as a novel biomarker and therapeutic target in the treatment of BLBCs in future.

Abstract 3014: Hyaluronan-mediated motility receptor maintains stemness and tumorigenic potential of glioblastoma stem cells

Abstract Glioblastoma (GBM) stem cells (GSCs) are a subpopulation of tumor cells that display stem-like characteristics (stemness) and play unique roles in tumor propagation, therapeutic resistance and tumor recurrence. It is becoming increasingly important to identify novel therapeutic targets in GSC for anti-GBM therapies. Here, we demonstrate that hyaluronan-mediated motility receptor (HMMR) is hyper-expressed in GBM tumors and supports the self-renewal and tumorigenic potential of GSCs. HMMR silencing impairs GSC self-renewal and inhibits the expression of GSC markers and regulators. HMMR silencing suppresses GSC-derived tumor growth and extends the survival of mice bearing GSC xenografts. HMMR overexpression promotes GSC self-renewal and intracranial tumor propagation. In human GBM tumor specimens, HMMR expression is positively correlated with the expression of cell-stemness-associated markers and regulators. Our findings identify HMMR as a potential therapeutic target for inhibiting GSCs, suggesting therapeutic applications against GBM. Citation Format: Jessica Tilghman, John Laterra, Mingyao Ying. Hyaluronan-mediated motility receptor maintains stemness and tumorigenic potential of glioblastoma stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3014. doi:10.1158/1538-7445.AM2014-3014

HMMR Maintains the Stemness and Tumorigenicity of Glioblastoma Stem-like Cells

Glioblastoma (GBM) stem cells (GSC) are a subpopulation of tumor cells that display stem-like characteristics (stemness) and play unique roles in tumor propagation, therapeutic resistance, and tumor recurrence. Therapeutic targets in GSCs are a focus of increasing interest to improve GBM therapy. Here we report that the hyaluronan-mediated motility receptor (HMMR) is highly expressed in GBM tumors, where it supports the self-renewal and tumorigenic potential of GSCs. HMMR silencing impairs GSC self-renewal and inhibits the expression of GSC markers and regulators. Furthermore, HMMR silencing suppresses GSC-derived tumor growth and extends the survival of mice bearing GSC xenografts. Conversely, HMMR overexpression promotes GSC self-renewal and intracranial tumor propagation. In human GBM tumor specimens, HMMR expression is correlated positively with the expression of stemness-associated markers and regulators. Our findings identify HMMR as a candidate therapeutic target to GSCs as a GBM treatment strategy.

Mechanism of MTA1 Protein Overexpression-linked Invasion: MTA1 REGULATION OF HYALURONAN-MEDIATED MOTILITY RECEPTOR (HMMR) EXPRESSION AND FUNCTION

Even though the hyaluronan-mediated motility receptor (HMMR), a cell surface oncogenic protein, is widely up-regulated in human cancers and correlates well with cell motility and invasion, the underlying molecular and nature of its putative upstream regulation remain unknown. Here, we found for the first time that MTA1 (metastatic tumor antigen 1), a master chromatin modifier, regulates the expression of HMMR and, consequently, its function in breast cancer cell motility and invasiveness. We recognized a positive correlation between the levels of MTA1 and HMMR in human cancer. Furthermore, MTA1 is required for optimal expression of HMMR. The underlying mechanism includes interaction of the MTA1·RNA polymerase II·c-Jun coactivator complex with the HMMR promoter to stimulates its transcription. Accordingly, selective siRNA-mediated knockdown of HMMR in breast cancer cells substantially reduces the invasion and migration of cells. These findings reveal a regulatory role for MTA1 as an upstream coactivator of HMMR expression and resulting biological phenotypes.

Effect of Reactive Oxygen on Hyaluronan Mediated Motility Receptor Expression in Osteoblasts

Effect of Reactive Oxygen on Hyaluronan Mediated Motility Receptor Expression in Osteoblasts