Epigenetic silencing of RELN in gastric cancer

Wakabayashi,

doi:10.3892/ijo_00000478

Cited by 22 publications

(3 citation statements)

References 21 publications

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“…More recent studies have described Reelin expression in non-neuronal tissues such as liver and kidney, as well as in normal breast tissue where it is necessary for mammary gland development [ 51 ]. Moreover, several studies have now shown that Reelin expression is reduced in many cancers, including breast cancer [ 23 , 24 , 25 ]. Interestingly, Reelin is differentially expressed within different breast cancer subtypes; Her2-positive breast tumors were found to express higher levels of Reelin compared to TNBC tumors and metastases [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…In human breast cancer biopsies, Reelin is expressed in adjacent, normal breast epithelium, but it is absent from cancerous tissue [ 23 ]. Various studies have since shown that the RELN gene is epigenetically silenced in breast cancer, as well as in other cancers such as gastric and pancreatic cancer [ 23 , 24 , 25 ]. Moreover, low RELN expression in breast cancer is associated with increased cancer cell migration, positive lymph node status, and poor prognosis [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Integrin α3β1 Represses Reelin Expression in Breast Cancer Cells to Promote Invasion

Ndoye

Miskin

DiPersio

2021

Cancers

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Integrin α3β1, a cell adhesion receptor for certain laminins, is known to promote breast tumor growth and invasion. Our previous gene microarray study showed that the RELN gene, which encodes the extracellular glycoprotein Reelin, was upregulated in α3β1-deficient (i.e., α3 knockdown) MDA-MB-231 cells. In breast cancer, reduced RELN expression is associated with increased invasion and poor prognosis. In this study we demonstrate that α3β1 represses RELN expression to enhance breast cancer cell invasion. RELN mRNA was significantly increased upon RNAi-mediated α3 knockdown in two triple-negative breast cancer cell lines, MDA-MB-231 and SUM159. Modulation of baseline Reelin levels altered invasive potential, where enhanced Reelin expression in MDA-MB-231 cells reduced invasion, while RNAi-mediated suppression of Reelin in SUM159 cells increased invasion. Moreover, treatment of α3β1-expressing MDA-MB-231 cells with culture medium that was conditioned by α3 knockdown MDA-MB-231 cells led to decreased invasion. RNAi-mediated suppression of Reelin in α3 knockdown MDA-MB-231 cells mitigated this effect of conditioned-medium, identifying secreted Reelin as an inhibitor of cell invasion. These results demonstrate a novel role for α3β1 in repressing Reelin in breast cancer cells to promote invasion, supporting this integrin as a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Integrin α3β1 Represses Reelin Expression in Breast Cancer Cells to Promote Invasion

Ndoye

Miskin

DiPersio

2021

Cancers

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“…Notably, alterations in Reelin expression are observed in cancers of nonneuronal origin (11). Specifically, the expression of Reelin is reduced in hepatocellular carcinoma, gastric carcinoma, colorectal cancer, glioblastoma, breast cancer, and pancreatic cancers (12)(13)(14)(15)(16)(17). In contrast, upregulation of Reelin is observed in retinoblastoma, esophageal carcinoma, high-grade prostate cancer, multiple myeloma, and non-Hodgkin lymphoma (18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Functional Heterogeneity of Reelin in the Oral Squamous Cell Carcinoma Microenvironment

Zhang

Ding

et al. 2021

Front. Oncol.

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BackgroundReelin, an extracellular glycoprotein, is expressed on neuronal cells and participates in neuronal migration during brain development. Recently, Reelin also has a vital role in carcinogenesis. However, its role in oral squamous cell carcinoma (OSCC) remains to be explored. The purpose of this study was to explore the roles of Reelin in OSCC.MethodsThe expression of Reelin in cancer-associated fibroblasts (ReelinCAF) and tumor cells (ReelinTC) was analyzed by the Gene Expression Omnibus (GEO) database. Immunohistochemistry (IHC) was used to detect the spatial pattern of Reelin in 75 OSCCs. The diagnostic and prognostic values of Reelin were evaluated and also verified by The Cancer Genome Atlas (TCGA) database. Primary CAFs from 13 OSCC patients were isolated to confirm Reelin expression. Thirty-nine OSCC peripheral blood samples were used to analyze the change of immunocytes based on Reelin levels by flow cytometry. The relationship between Reelin and tumor immune microenvironment in head and neck squamous cell carcinoma (HNSCC) tissues was determined by TISIDB and the Tumor Immune Estimation Resource (TIMER) database.ResultsIn breast cancer, pancreatic cancer and rectal cancer, Reelin in CAFs was significantly upregulated compared with Reelin in TCs. The IHC results in OSCC also showed that Reelin levels were higher in CAFs. Upregulated ReelinTC was related to a decreased pN stage and distant metastasis. Strikingly, patients with enhanced ReelinCAF had a high risk of lymph node metastasis, poor worst pattern of invasion (WPOI), and distant metastasis, but showed comparable Ki-67 level in all OSCC patients, resulting in shorter overall survival (OS) and disease-specific survival (DSS). Unexpectedly, Reelin in tumor-infiltrating lymphocytes (ReelinTIL) was correlated with postoperative relapse. Patients with high ReelinTIL, but not ReelinTC and ReelinCAF, had poor cytotoxicity of CD8+ T cells and higher ratio of CD4/CD8 in peripheral blood. However, Reelin was positively associated with tissue-resident B cells and NK cells in the tumor microenvironment.ConclusionReelin has a versatile function in distinct cell types during the development of OSCC via governing tumor cell and stroma microenvironment.

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Analysis of genomic and immune intratumor heterogeneity in linitis plastica via multiregional exome and T‐cell receptor sequencing

et al. 2023

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The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole‐exome sequencing (WES) and T‐cell receptor (TCR) sequencing on 40 tumor regions from four LP patients. The landscape and ITH at the genomic and immunological levels in LP tumors were compared with multiple cancers that have previously been reported. The lymphocyte infiltration was further assessed by immunohistochemistry (IHC) in LP tumors. In total, we identified 6339 non‐silent mutations from multi‐samples, with a median tumor mutation burden (TMB) of 3.30 mutations per Mb, comparable to gastric adenocarcinoma from the Cancer Genome Atlas (TCGA) cohort (P = 0.53). An extremely high level of genomic ITH was observed, with only 12.42%, 5.37%, 5.35%, and 30.67% of mutations detectable across 10 regions within the same tumors of each patient, respectively. TCR sequencing revealed that TCR clonality was substantially lower in LP than in multi‐cancers. IHC using antibodies against CD4, CD8, and PD‐L1 demonstrated scant T‐cell infiltration in the four LP tumors. Furthermore, profound TCR ITH was observed in all LP tumors, with no T‐cell clones shared across tumor regions in any of the patients, while over 94% of T‐cell clones were restricted to individual tumor regions. The Morisita overlap index (MOI) ranged from 0.21 to 0.66 among multi‐regions within the same tumors, significantly lower than that of lung cancer (P = 0.002). Our results show that LP harbored extremely high genomic and TCR ITH and suppressed T‐cell infiltration, suggesting a potential contribution to the frequent recurrence and poor therapeutic response of this adenocarcinoma.

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Epigenetic silencing of RELN in gastric cancer

Cited by 22 publications

References 21 publications

Integrin α3β1 Represses Reelin Expression in Breast Cancer Cells to Promote Invasion

Integrin α3β1 Represses Reelin Expression in Breast Cancer Cells to Promote Invasion

Functional Heterogeneity of Reelin in the Oral Squamous Cell Carcinoma Microenvironment

Analysis of genomic and immune intratumor heterogeneity in linitis plastica via multiregional exome and T‐cell receptor sequencing

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