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[This corrects the article DOI: 10.3389/fphar.2024.1361424.].

The Ryukyu archipelago is located southwest of the Japanese islands, and people originally from this region, the Ryukyu population, have a unique genetic background distinct from that of other populations, including people from mainland Japan. However, few genetic studies have focused on the Ryukyu population. In this study, we performed genome-wide association studies (GWAS) on the serum levels of alanine aminotransferase (ALT, n = 15,224), aspartate aminotransferase (AST, n = 15,203), and gamma-glutamyl transferase (GGT, n = 14,496) in the Ryukyu population. We found 13 loci with a genome-wide significant association ( P  < 5 × 10 −8 ), three for ALT, four for AST, and six for GGT, including one novel locus associated with ALT: rs117595134-A in HMMR / HMMR-AS1 , ß =  − 0.131, standard error = 0.024, P  = 4.90 × 10 −8 . Rs117595134-A is common in the Japanese population but is not observed in other ethnic populations in the 1000 genomes database. Additionally, 77 of 80 loci derived from Korean GWAS and 541 of 716 loci from European GWAS showed the same directions of effect ( P  = 1.41 × 10 −19 , P  = 2.50 × 10 −44 , binomial test), indicating that most of susceptibility loci are shared between the Ryukyu population and other ethnic populations.

Circ₀005273 was increased in BC tissues and cells, and its knockdown might repress BC cell proliferation, migration, invasion, glutamine metabolism, and induce apoptosis partly by regulating the miR‐509‐3p/HMMR axis.

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.

Among women, breast carcinoma is one of the most complex cancers, with one of the highest death rates worldwide. There have been significant improvements in treatment methods, but its early detection still remains an issue to be resolved. This study explores the multifaceted function of hyaluronan-mediated motility receptor (HMMR) in breast cancer progression. HMMR’s association with key cell cycle regulators (AURKA, TPX2, and CDK1) underscores its pivotal role in cancer initiation and advancement. HMMR’s involvement in microtubule assembly and cellular interactions, both extracellularly and intracellularly, provides critical insights into its contribution to cancer cell processes. Elevated HMMR expression triggered by inflammatory signals correlates with unfavorable prognosis in breast cancer and various other malignancies. Therefore, recognizing HMMR as a promising therapeutic target, the study validates the overexpression of HMMR in breast cancer and various pan cancers and its correlation with certain proteins such as AURKA, TPX2, and CDK1 through online databases. Furthermore, the pathways associated with HMMR were explored using pathway enrichment analysis, such as Gene Ontology, offering a foundation for the development of effective strategies in breast cancer treatment. The study further highlights compounds capable of inhibiting certain pathways, which, in turn, would inhibit the upregulation of HMMR in breast cancer. The results were further validated via MD simulations in addition to molecular docking to explore protein–protein/ligand interaction. Consequently, these findings imply that HMMR could play a pivotal role as a crucial oncogenic regulator, highlighting its potential as a promising target for the therapeutic intervention of breast carcinoma.

Hyaluronan-mediated motility receptor (HMMR) is overexpressed in multiple carcinomas and influences the development and treatment of several cancers. However, its role in hepatocellular carcinoma (HCC) remains unclear. The \"limma\" and \"GSVA\" packages in R were used to perform differential expression analysis and to assess the activity of signalling pathways, respectively. InferCNV was used to infer copy number variation (CNV) for each hepatocyte and \"CellChat\" was used to analyse intercellular communication networks. Recursive partitioning analysis (RPA) was used to re-stage HCC patients. The IC values of various drugs were evaluated using the \"pRRophetic\" package. In addition, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to confirm HMMR expression in an HCC tissue microarray. Flow cytometry (FCM) and cloning, Edu and wound healing assays were used to explore the capacity of HMMR to regulate HCC tumour. Multiple cohort studies and qRT-PCR demonstrated that HMMR was overexpressed in HCC tissue compared with normal tissue. In addition, HMMR had excellent diagnostic performance. HMMR knockdown inhibited the proliferation and migration of HCC cells . Moreover, high HMMR expression was associated with \"G2M checkpoint\" and \"E2F targets\" in bulk RNA and scRNA-seq, and FCM confirmed that HMMR could regulate the cell cycle. In addition, HMMR was involved in the regulation of the tumour immune microenvironment via immune cell infiltration and intercellular interactions. Furthermore, HMMR was positively associated with genomic heterogeneity with patients with high HMMR expression potentially benefitting more from immunotherapy. Moreover, HMMR was associated with poor prognosis in patients with HCC and the re-staging by recursive partitioning analysis (RPA) gave a good prognosis prediction value and could guide chemotherapy and targeted therapy. The results of the present study show that HMMR could play a role in the diagnosis, prognosis, and treatments of patients with HCC based on bulk RNA-seq and scRAN-seq analyses and is a promising molecular marker for HCC.

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.

Background RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM +ve cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM impacts cell cycle progression and cell migration. However, the RHAMM functions that contribute to breast cancer metastasis are poorly understood. Methods We interrogated the metastatic functions of RHAMM using a loss-of-function approach by crossing the MMTV-PyMT mouse model of breast cancer susceptibility with Rhamm −/− mice. In vitro analyses of known RHAMM functions were performed using primary tumor cell cultures and MMTV-PyMT cell lines. Somatic mutations were identified using a mouse genotyping array. RNA-seq was performed to identify transcriptome changes resulting from Rhamm -loss, and SiRNA and CRISPR/Cas9 gene editing was used to establish cause and effect of survival mechanisms in vitro. Results Rhamm -loss does not alter initiation or growth of MMTV-PyMT-induced primary tumors but unexpectedly increases lung metastasis. Increased metastatic propensity with Rhamm -loss is not associated with obvious alterations in proliferation, epithelial plasticity, migration, invasion or genomic stability. SNV analyses identify positive selection of Rhamm −/− primary tumor clones that are enriched in lung metastases. Rhamm −/− tumor clones are characterized by an increased ability to survive with ROS-mediated DNA damage, which associates with blunted expression of interferon pathway and target genes, particularly those implicated in DNA damage-resistance. Mechanistic analyses show that ablating RHAMM expression in breast tumor cells by siRNA knockdown or CRISPR-Cas9 gene editing blunts interferon signaling activation by STING agonists and reduces STING agonist-induced apoptosis. The metastasis-specific effect of RHAMM expression-loss is linked to microenvironmental factors unique to tumor-bearing lung tissue, notably high ROS and TGFB levels. These factors promote STING-induced apoptosis of RHAMM +ve tumor cells to a significantly greater extent than RHAMM −ve comparators. As predicted by these results, colony size of Wildtype lung metastases is inversely related to RHAMM expression. Conclusion RHAMM expression-loss blunts STING-IFN signaling, which offers growth advantages under specific microenvironmental conditions of lung tissue. These results provide mechanistic insight into factors controlling clonal survival/expansion of metastatic colonies and has translational potential for RHAMM expression as a marker of sensitivity to interferon therapy.

Acute lymphoblastic leukemia (ALL) is a malignant neoplasm with the highest incidence in the pediatric population. Although the 5-year overall survival is greater than 85%, in emerging countries such as Mexico, the mortality rate is high. In Mexico, B-ALL is the most common type of childhood cancer; different characteristics suggest the presence of the disease; however, the prognosis is dependent on clinical and laboratory features, and no adverse prognostic molecular marker for B-ALL has yet been identified. The present research aimed to identify the prognostic value of HMMR expression in pediatric patients with B-ALL. The differential expression profile of B-ALL cells was determined via in silico analysis, and HMMR expression was subsequently measured via qRT–PCR and immunocytochemistry. The results were statistically analyzed via the ROUT test, Kolmogorov–Smirnov Z test, and Mann–Whitney U test. ROC curves and the Youden index were constructed, and Kaplan–Meier curves were plotted. We found that HMMR expression was increased in B-ALL patients (p < 0.0001). We observed that high expression was related to poor prognosis (p < 0.05). We observed that high expression was related to poor prognosis (p < 0.05). The increase in HMMR expression could be a potential early molecular prognostic marker and/or a new target in childhood B-ALL patients.

Neuroblastoma (NB) is a devastating childhood cancer where most tumours have no clear oncogenic driver. We aimed to define whether HMMR, an oncogene-like protein in several cancers, harbors similar potential in neuroblastoma cells. HMMR is a hyaluronic acid (HA) receptor and a mitotic microtubule regulator. We show that high HMMR expression does not correlate well with MYCN driver expression and moreover statistically HMMR is an independent prognostic indicator of poor survival in NB patients. In cultured KELLY neuroblastoma cells, removal of the HMMR protein suppresses proliferation, motility and clonogenic capacity, while xenografts of HMMR-deficient cells imparted longer animal survival compared to wild type cells. Loss of motility in culture was compensated by addition of exogenous HA, suggesting that HMMR signaling is at least partly under HA control. Through an unbiased phosphoproteomic analysis, we also found that signaling downstream of MAPK1/2 was disrupted after loss of HMMR. In addition, RPS6 and p70S6 kinase were hypophosphorylated, while the DNA damage response (DDR) proteins such as CHK2 and TP53BP1 were significantly hyperphosphorylated. We thus provide, for the first time, evidence that HMMR does have oncoprotein-like properties in neuroblastoma cells and that HMMR expression has potential as a prognostic marker. Moreover, initial biochemical analyses highlight a potential influence for HMMR in MTOR and DDR pathway regulation.