HMMR associates with immune infiltrates and acts as a prognostic biomaker in lung adenocarcinoma

https://doi.org/10.1016/j.compbiomed.2022.106213Get rights and content

Highlights

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    HMMR has an effect on the occurrence and development of lung adenocarcinoma.

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    HMMR is linked to the expression level of neutrophils, CD8+T cells, and CD4+T cells and LUAD patients' prognosis.

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    HMMR could become a biomarker or therapeutic target to judge the prognosis and immune infiltration of LUAD.

Abstract

Background

To explore the expression of hyaluronan mediated motility receptor (HMMR) in lung adenocarcinoma (LUAD) and its relationship with clinicopathological features and tumor-infiltrating is not clear.

Methods

The expression of HMMR in Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA)-LUAD. TCGA was employed to examine the relationship between the clinicopathological characteristics and HMMR expression and the LUAD patients’ prognosis. Tumor Immune Estimation Resource (TIMER)database was employed to analyze the relationship between immune infiltration and HMMR. Gene Set Enrichment Analysis was explored through gene enrichment. Gene Expression Omnibus (GEO) data and our hospital data were utilized to confirm the findings.

Results

The expression level of HMMR in lung adenocarcinoma tissue and cells was greater than that in the normal group, which was linked to clinical stage, smoking history, and recurrence, and could increase the progression or recurrence of LUAD. Patients in the pathological grade had a significant expression of HMMR in moderately differentiated LUAD tissues. In addition, HMMR has an impact on LUAD patients’ overall survival rate [P = 9.5e-06; hazard ratio (HR) = 2]. The level of HMMR expression in LUAD was significantly linked to neutrophils, CD8+T, and CD4+T cells. TMB analysis showed that HMMR could also affect the tumor microenvironment in LUAD. HMMR might be employed as an independent predictive biomarker of LUAD, according to a multivariate COX regression analysis. The findings of GSEA analysis showed that the samples with high HMMR expression levels were rich in cell cycle, cell metabolism, and DNA replication. The analysis results of GSE31210 data are basically consistent with those of TCGA-LUAD.

Conclusions

It is suggested that HMMR has an effect on the occurrence and development of lung adenocarcinoma. Besides, HMMR is also linked to the level of immune infiltration of neutrophils, CD8+T cells, and CD4+T cells and LUAD patients’ prognosis. HMMR was suggested to be utilized as a biomarker or therapeutic target to judge the prognosis and immune infiltration of LUAD.

Introduction

Lung cancer has the greatest morbidity and fatality rate in both men and women worldwide [1]. The two most common subtypes of lung cancer are non-small cell lung cancer (NSCLC) with a prevalence of approximately 85% and small cell lung cancer [2]. It is believed that lung adenocarcinoma (LUAD) contributes to more than 40% of NSCLC cases, thus ranking the greatest common and invasive pathological type of NSCLC. In addition, it is the major cause of cancer-associated mortalities [3]. Due to the slow growth of LUAD and the absence of particular clinical characteristics in the early stage, the rate of early diagnosis is not high [4,5]. With the improvement of current clinical diagnostic approaches such as imaging techniques, although the overall survival rate has been improved, it is still not satisfactory, with a 5-year survival rate of no more than 15% [6]. Therefore, finding effective tumor markers to guide clinical diagnosis and treatment approaches necessitated the need to carry out the LUAD experiment.

Hyaluronan Mediated Motility Receptor (HMMR), also named CD168, is a coding gene located on chromosome 5 [7,8]. Previous studies indicated that HMMR affected cell cycle and division by affecting the function of the macrophage polarization and promoting epithelial-to-mesenchymal transition [9,10]. Moreover, HMMR protein was associated with numerous tumor types, such as acute myeloid leukemia [11,12], breast cancer [[13], [14], [15]], sarcoma [16], and lung cancer [17,18]. These results suggested that HMMR acted a significant function in both the occurrence and progression of cancer, as well as in cancer metastasis.

The expression of HMMR is a specific feature of regulatory T lymphocytes (Treg) infiltrated by breast cancer and acute myeloid leukemia. Additionally, HMMR expression was linked to poor prognosis in both breast cancer and sarcoma patients [14,16]. The previous research demonstrated that HMMR was a vital gene related to acute myeloid leukemia tumor-infiltrating lymphocytes [19]. These data suggested that HMMR played a multifaceted role in tumor-infiltrating T cells and Treg cells. Nevertheless, the basic role and mechanism of HMMR in both immunology and the progression of tumors is still uncertain.

In our research, our team evaluated the expression of HMMR and its correlation with the prognosis of participants with LUAD in GEPIA, UALCAN, STRING, and GEO databases. Furthermore, we utilized the TIMER database to examine the link between HMMR and tumor-infiltrating immune cells in the LUAD tumor microenvironment. This experiment's findings clarified the important role of HMMR in lung adenocarcinoma and revealed the potential mechanism and relationship between tumor-immune interaction and HMMR.

Section snippets

Patient samples

In total, 64 patient samples with LUAD devoid of exposure to radiotherapy and chemotherapy exposure before the surgical procedure were collected from Chinese PLA General Hospital. Subsequently, the samples were frozen in liquid nitrogen and kept at a temperature of −80 °C for RNA extraction. The Ethics Committee of Chinese PLA General Hospital granted its approval for this experiment. Besides, all patients recruited in this experiment signed informed consent forms.

RNA extraction and qRT-PCR

The total RNA from tissues was

The mRNA expression levels of HMMR in NSCLC

According to CCLE database data, NSCLC ranks 12th of all cancer cell lines in terms of HMMR expression, and more abundance was concentrated in immune cells (Fig. 1A). In order to obtain a more accurate expression of HMMR in NSCLC and normal lung samples, we acquired the expression of LUAD and LUSC in TCGA and the prognostic significance of HMMR, respectively (Fig. 1B–E). Surprisingly, HMMR has prognostic significance in LUAD, while LUSC does not. Therefore, we selected the subtype of LUAD in

Discussion

In our research, we assessed the expression of HMMR in LUAD based on the TCGA database and discussed its relationship with function, clinicopathological features, immune infiltration, co-expression, and survival. Understanding whether the high expression of HMMR in tumors is directly related to LUAD is helpful for us to understand the mechanism of clinical survival patterns. In our results, the high expression of HMMR indicated that HMMR might play a critical function in regulating tumor

Ethical approval and informed consent

All procedures performed in studies involving human participants were performed in accordance with the Declaration of Helsinki and approved the Ethics Committee of Chinese PLA General Hospital granted its approval for this study, and all participants or their guardians signed written informed consent.

Consent for publication

Not applicable.

Authors' contributions

The experiments were designed and performed by XDM, YYW and JXW. Data were examined by YYW, MX, JY, XYX, and ZQX. This manuscript was written by all of the authors. The final manuscript was reviewed and approved by all authors.

Data availability statement

The data supporting this study's findings are publicly accessible in TCGA at https://cancergenome.nih.gov/and GEO at https://www.ncbi.nlm.nih.gov/geo/, with reference numbers of GSE8894, GSE37745, and GSE31210.

Declaration of competing interest

There is no conflict of interest, according to the authors.

Acknowledgments

We acknowledge the financial support from the following organizations: Ministry of Education's Research and innovation fund (2018A03026), National Natural Science Foundation of China (62176166, 62076254), Beijing Natural Science Foundation (2019A10), and Beijing Municipal Hospital Administration “Qingmiao” plan (2018QM4).

References (36)

  • F. Mateo et al.

    Modification of BRCA1-associated breast cancer risk by HMMR overexpression

    Nat. Commun.

    (2022)
  • X. Jiang et al.

    NcRNA-mediated high expression of HMMR as a prognostic biomarker correlated with cell proliferation and cell migration in lung adenocarcinoma

    Front. Oncol.

    (2022)
  • X. Wang et al.

    Exosomal lncRNA HMMR-AS1 mediates macrophage polarization through miR-147a/ARID3A axis under hypoxia and affects the progression of hepatocellular carcinoma

    Environ. Toxicol.

    (2022)
  • S. Juarez-Mendez et al.

    Hyalurionan-mediate motility receptor (HMMR) expression predicts overall survival in childhood B-cell acute lymphoblastic leukemia

    Pediatr. Blood Cancer

    (2019)
  • J.T. Isakova et al.

    Gene-to-gene interactions and the association of TP53, XRCC1, TNF alpha, HMMR, MDM2 and PALB2 with breast cancer in Kyrgyz females

    Breast Cancer

    (2020)
  • N.P. Akent'eva et al.

    Effects of RHAMM/HMMR-Selective peptides on survival of breast cancer cells

    Bull. Exp. Biol. Med.

    (2015)
  • B. Bidadi et al.

    Pathway-based analysis of genome-wide association data identified SNPs in HMMR as biomarker for chemotherapy-induced Neutropenia in breast cancer patients

    Front. Pharmacol.

    (2018)
  • S. Ye et al.

    TGF beta and Hippo pathways cooperate to Enhance sarcomagenesis and metastasis through the hyaluronan-mediated motility receptor (HMMR)

    Mol. Cancer Res.

    (2020)
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    These authors contributed equally to this work.

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