Immunohistochemical analysis of RHAMM expression in normal and neoplastic human tissues: a cell cycle protein with distinctive expression in mitotic cells and testicular germ cells.

Yao-Tseng Chen,Yi-Chieh Nancy Du,Zhengming Chen

doi:10.18632/oncotarget.24939

Yao-Tseng Chen, Yi-Chieh Nancy Du + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.24939

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Journal: Oncotarget	Publication Date: Apr 20, 2018
Citations: 30	License type: cc-by

Affiliation: Cornell University

Abstract

Expression of Receptor for Hyaluronic Acid Mediated Motility (RHAMM) increases cellular motility and RHAMM overexpression promotes invasive phenotype and metastasis of cancer cells. RHAMM has been suggested as a biomarker for poor prognosis in several tumor types, including lung, breast, colorectal, gastric, pancreatic ductal, and ovarian cancers. RNA studies showed restricted RHAMM expression in normal tissues, but its protein expression data in tissues were limited. In light of its potential as a prognostic marker and a therapeutic target, we performed immunohistochemical analysis to systematically characterize RHAMM expression in normal and neoplastic human tissues. Among 29 normal adult tissues, RHAMM protein showed restricted expression and was observed in the thymus, lymph node/tonsil, small intestine, colon, skin, bone marrow, placenta, and testis. The cellular distribution patterns of RHAMM in these normal tissues were consistent with RHAMM being a G2/M cell cycle protein, and this was further supported in comparison to the expression of cyclin B2, another G2/M protein. However, unlike the subcellular localization of cyclin B2, RHAMM decorated mitotic spindles in both anaphase and metaphase. RHAMM expression in tumor tissues is variable; and higher RHAMM protein expression is associated with histologically higher-grade tumors in general. Distinct from its expression in somatic tissues, RHAMM showed diffuse, strong, stage-specific expression in the spermatocyte stage of germ cells in adult testis. The neoplastic counterpart, spermatocytic tumor, also showed strong RHAMM expression. This unique expression in testis suggests that RHAMM may function during normal testicular germ cell maturation.

Highlights

Receptor for Hyaluronic Acid Mediated Motility (RHAMM, CD168) was initially identified as a protein that binds to hyaluronic acid [1]
We demonstrated that 96% of metastatic non-small lung cancer expressed RHAMM proteins, and RHAMM mRNA expression correlated with shortened www.oncotarget.com survival in lung adenocarcinoma [7]
We found RHAMM protein expression to be restricted to the intestinal tract, skin, bone marrow, lymph node, tonsil, thymus, placenta, and testis (Figure 1 and Table 1)

Summary

Introduction

Receptor for Hyaluronic Acid Mediated Motility (RHAMM, CD168) was initially identified as a protein that binds to hyaluronic acid (hyaluronan or HA) [1]. Increased production of hyaluronic acid has been correlated with increased migration and invasion in aggressive cancers. Alternative mRNA splicing leads to four RHAMM isoforms, and we identified the gene product of RHAMM isoform B (RHAMMB) to promote liver metastasis of pancreatic neuroendocrine tumors [6]. We demonstrated that 96% of metastatic non-small lung cancer expressed RHAMM proteins, and RHAMM mRNA expression correlated with shortened www.oncotarget.com survival in lung adenocarcinoma [7]. Short hairpin RNA (shRNA)-mediated knockdown of RHAMM reduced the migratory ability of lung adenocarcinoma cells, suggesting that RHAMM is a prognostic factor and contributes to lung cancer metastasis. Other studies have shown that RHAMM upregulation is a prognostic indicator for breast cancer, colorectal cancer, endometrial carcinomas, large cell lung cancer, gastric cancer, pancreatic ductal adenocarcinoma, and ovarian cancer [8,9,10,11,12,13,14,15]

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