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GalNAc 型 O-聚糖的截断抑制乳腺癌中 CD44 介导的破骨细胞生成和骨转移。

Truncation of GalNAc-type O-glycans Suppresses CD44-mediated Osteoclastogenesis and Bone Metastasis in Breast Cancer.

机构信息

Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Department of Plastic and Reconstructive Surgery, China Medical University Hospital, Taichung, Taiwan.

出版信息

Mol Cancer Res. 2023 Jul 5;21(7):664-674. doi: 10.1158/1541-7786.MCR-22-0907.

DOI:10.1158/1541-7786.MCR-22-0907
PMID:37040171
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10320474/
Abstract

UNLABELLED

The glycoprotein CD44 is a key regulator of malignant behaviors in breast cancer cells. To date, hyaluronic acid (HA)-CD44 signaling pathway has been widely documented in the context of metastatic bone diseases. Core 1 β1,3-galactosyltransferase (C1GALT1) is a critical enzyme responsible for the elongation of O-glycosylation. Aberrant O-glycans is recognized as a hallmark in cancers. However, the effects of C1GALT1 on CD44 signaling and bone metastasis remain unclear. In this study, IHC analysis indicated that C1GALT1 expression positively correlates with CD44 in breast cancer. Silencing C1GALT1 accumulates the Tn antigen on CD44, which decreases CD44 levels and osteoclastogenic signaling. Mutations in the O-glycosites on the stem region of CD44 impair its surface localization as well as suppress cell-HA adhesion and osteoclastogenic effects of breast cancer cells. Furthermore, in vivo experiments demonstrated the inhibitory effect of silencing C1GALT1 on breast cancer bone metastasis and bone loss. In conclusion, our study highlights the importance of O-glycans in promoting CD44-mediated tumorigenic signals and indicates a novel function of C1GALT1 in driving breast cancer bone metastasis.

IMPLICATIONS

Truncation of GalNAc-type O-glycans by silencing C1GALT1 suppresses CD44-mediated osteoclastogenesis and bone metastasis in breast cancer. Targeting the O-glycans on CD44 may serve as a potential therapeutic target for blocking cancer bone metastasis.

摘要

未加标签

糖蛋白 CD44 是乳腺癌细胞恶性行为的关键调节因子。迄今为止，透明质酸（HA）-CD44 信号通路已在转移性骨疾病的背景下得到广泛研究。核心 1 β1,3-半乳糖基转移酶（C1GALT1）是负责 O-糖基化延长的关键酶。异常的 O-聚糖被认为是癌症的一个标志。然而，C1GALT1 对 CD44 信号和骨转移的影响尚不清楚。在这项研究中，免疫组化分析表明 C1GALT1 的表达与乳腺癌中的 CD44 呈正相关。沉默 C1GALT1 会在 CD44 上积累 Tn 抗原，从而降低 CD44 水平和破骨细胞信号。CD44 茎区 O-糖基化位点的突变会损害其表面定位，并抑制细胞-HA 黏附和乳腺癌细胞的破骨细胞生成作用。此外，体内实验表明沉默 C1GALT1 可抑制乳腺癌骨转移和骨丢失。总之，我们的研究强调了 O-聚糖在促进 CD44 介导的肿瘤发生信号中的重要性，并表明 C1GALT1 在驱动乳腺癌骨转移中的新功能。

含义

通过沉默 C1GALT1 截断 GalNAc 型 O-聚糖可抑制 CD44 介导的破骨细胞生成和乳腺癌骨转移。靶向 CD44 上的 O-聚糖可能成为阻断癌症骨转移的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/505f00e631c0/664fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/c0b18b2ffa0d/overview_graphic_mcr-22-0907.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/050e4d8e95e6/664fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/f13a0d2f7c1e/664fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/b4f7029d11ac/664fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/b5604c794753/664fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/32aebfcc96ea/664fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/505f00e631c0/664fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/c0b18b2ffa0d/overview_graphic_mcr-22-0907.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/050e4d8e95e6/664fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/f13a0d2f7c1e/664fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/b4f7029d11ac/664fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/b5604c794753/664fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/32aebfcc96ea/664fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0493/10320474/505f00e631c0/664fig6.jpg

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