HMMR in human cancers: regulatory mechanism and biological function

Hu et al. Journal of Translational Medicine (2025) 23:1302 https://doi.org/10.1186/s12967-025-07260-1 Journal of Translational Medicine Open Access REVIEW HMMR in human cancers: regulatory mechanism and biological function Yanghao Hu1,2†, Yifei Zhang1,2†, Jiali He1,2, Huihuang Rao1,2, Zhengyu Wei3, Zhisen Shen1* and Chongchang Zhou1* Abstract Hyaluronan-mediated motility receptor (HMMR), also referred to as RHAMM or CD168, has gained recognition as a multifunctional protein that mediates the transmission of extracellular matrix-derived hyaluronan (HA) signals to intracellular pathways regulating tumor growth, migration, and mitosis. Overexpression of HMMR is observed in various cancers, including head and neck squamous cell carcinoma, breast cancer, lung cancer, and prostate cancer, as well as several hematologic malignancies. This elevated expression correlates with poor prognosis, rendering it a valuable marker for survival prediction and risk stratification. Functionally, HMMR facilitates tumor progression and metastasis by activating multiple oncogenic pathways and coordinating spindle assembly, cell polarity, and mitotic fidelity. Additionally, HMMR plays a key role forming an immunosuppressive tumor microenvironment and supporting the maintenance of cancer stem cells, collectively driving metastasis, therapeutic resistance, and adverse clinical outcomes. These diverse functions position HMMR as both a promising prognostic biomarker and a potential therapeutic target. However, its coiled-coil structural characteristics present significant challenges for traditional small-molecule inhibition. In response, emerging strategies such as peptide mimetics that competitively inhibit HA binding, HMMR-based tumor vaccines, and HA synthesis inhibitors are being explored to counteract HMMR-driven oncogenic activities. This review offers a comprehensive overview of HMMR‘s discovery, structural domains, isoform diversity, upstream regulatory networks, and key signaling pathways, underscoring its biological relevance and clinical significance across various cancers while clarifying the tumor and context specific roles of HMMR and its structural and functional complexity. Keywords HMMR, Biomarker, Cancer progression and metastasis, Immunosuppressive tumor microenvironment, Therapeutic targeting † Yanghao Hu and Yifei Zhang contributed equally to this work. *Correspondence: Zhisen Shen Chongchang Zhou 1 Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China 2 Ningbo University Health Science Center, Ningbo University, Ningbo, Zhejiang, China 3 Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China © The Author(s) 2025. 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To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Hu et al. Journal of Translational Medicine (2025) 23:1302 Background Hyaluronan (HA) is a linear, water-soluble polysaccharide composed of alternating N-acetylglucosamine and D-glucuronic acid units linked by β-1,4- and β-1,3glycosidic bonds [1]. As a key component of the extracellular matrix (ECM), HA is primarily localized in soft connective tissues [2] and plays critical roles in various biological processes, including tissue development, inflammation, and cancer progression [3–5]. The biological functions of HA are regulated by its unique physical properties, dynamic turnover, and interactions with specific cell surface receptors [6]. Under physiological conditions, high molecular weight HA ( > 900 kDa) predominates, contributing to tissue homeostasis, antiinflammatory responses, and wound repair [7]. HA exerts its biological effects by binding to specific cell surface receptors, including Lymphatic Vessel Endothelial Hyaluronan Receptor-1, Cluster of Differentiation 44 (CD44), Hyaluronan-Mediated Motility Receptor (HMMR), Layilin, and Toll-like Receptor 2 [1, 6]. CD44, the most extensively studied HA receptor, is widely expressed in embryonic stem cells, bone marrow, and connective tissues [8, 9]. It also interacts with ligands such as collagen and osteopontin to regulate cell adhesion, migration, and signaling [10, 11]. Notably, CD44 is significantly upregulated in specific cancer subpopulations, particularly those undergoing epithelial-mesenchymal transition (EMT), which enhances invasiveness and chemoresistance, making it a critical tumor biomarker [12, 13]. HMMR (also known as RHAMM, CD168, or IHABP) is another important HA receptor, expressed in a variety of cell types, including fibroblasts, smooth muscle cells, macrophages, and lymphocytes [14]. HMMR preferentially binds to low-molecular weight HA (LMW-HA; < 120–250 kDa), which is often enriched in pathological conditions and correlates with enhanced cell proliferation, motility, inflammation, M1 macrophage polarization, and ECM remodeling [7]. HMMR plays a pivotal role in the progression and poor prognosis of several cancers, including breast cancer [15], head and neck squamous cell carcinoma (HNSCC) [16], and B cell acute lymphoblastic leukemia (ALL) [17]. Elevated HMMR expression is strongly linked to reduced overall survival (OS) in cancer patients [18], highlighting its potential as a prognostic biomarker. At the molecular level, HMMR is regulated by a complex network of transcription factors and signaling pathways, contributing to cancer progression and invasion through multiple oncogenic routes. This review provides a comprehensive summary of the discovery and structural features of HMMR, and elaborates on its functional roles in tumor development and metastasis. It outlines the upstream regulatory mechanisms and downstream signaling pathways involved in Page 2 of 28 oncogenic processes, with particular emphasis on the biological functions and clinical significance of HMMR, advancing our understanding of cancer biology and offering a foundation for developing novel diagnostic, prognostic, and therapeutic strategies target (...truncated)