Chondroitin Sulfates Control Invasiveness of the Basal-Like Breast Cancer Cell Line MDA-MB-231 Through ROR1.
Chondroitin Sulfates Control Invasiveness of the Basal-Like Breast Cancer Cell Line MDA-MB-231 Through ROR1.
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DOI：
10.3389/fonc.2022.914838
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发表时间：
2022
影响因子：
4.7
通讯作者：
Kitagawa, Hiroshi
中科院分区：
文献类型：
--
作者：
Nadanaka, Satomi;Tamura, Jun-ichi;Kitagawa, Hiroshi
关键词：
细胞外和细胞表面的硫酸软骨素（CS）调节癌细胞的特性，包括增殖和侵袭。因此，有必要了解它们在癌症中所起作用的潜在机制。尽管我们已经表明CS具有增强人三阴性乳腺癌细胞系MDA - MB - 231侵袭活性的固有能力，但其分子机制仍然不清楚。在此，我们聚焦于受体酪氨酸激酶样孤儿受体1（ROR1）和 dickkopf WNT信号通路抑制剂1（DKK1）。MDA - MB - 231细胞高水平表达ROR1；它们的侵袭潜能依赖于ROR1信号。尽管越来越多的证据表明ROR1与侵袭性乳腺癌表型相关，但其生物学功能的全貌仍知之甚少。在这项研究中，我们检测了CS是否控制ROR1的功能。表面等离子体共振分析表明，在WNT5A存在的情况下，CS与ROR1结合。通过RNA干扰技术降低ROR1的表达可完全抑制CS增强的MDA - MB - 231细胞的侵袭活性。此外，即使在ROR1存在的情况下，降低CS生物合成酶CHST11和CHST15的表达也可抑制侵袭活性。这些结果表明，CS是诱导依赖于ROR1的侵袭性MDA - MB - 231表型所必需的。MDA - MB - 231细胞中的ROR1信号激活c - Jun N - 末端激酶（JNK），导致侵袭潜能增加；此外，外源性CS激活JNK。MDA - MB - 231细胞高水平表达DKK1，它是一种与CS结合的肿瘤抑制因子。降低DKK1的表达增强了CS刺激的MDA - MB - 231细胞的肿瘤侵袭活性，这表明DKK1隔离CS以阻断ROR1/JNK信号。这些结果表明，在MDA - MB - 231细胞中，CS通过ROR1 - JNK轴促进癌症的侵袭性。
Extracellular and cell surface chondroitin sulfates (CSs) regulate cancer cell properties, including proliferation and invasion. Thus, it is necessary to understand the mechanisms underlying their roles in cancer. Although we have shown that CS has an inherent ability to enhance the invasive activity of the human triple-negative breast cancer cell line MDA-MB-231, its molecular mechanism remains elusive. Here, we focused on receptor tyrosine kinase-like orphan receptor 1 (ROR1) and dickkopf WNT signaling pathway inhibitor 1 (DKK1). MDA-MB-231 cells express high levels of ROR1; their invasive potential depends on ROR1 signaling. Although accumulating evidence has demonstrated that ROR1 is associated with aggressive breast-cancer phenotypes, the whole picture of its biological function remains poorly understood. In this study, we examined whether CS controls ROR1 function. Surface plasmon resonance analysis indicated that CSs were bound to ROR1 in the presence of WNT5A. The invasive activity of MDA-MB-231 cells enhanced by CSs was completely suppressed by ROR1 knockdown. In addition, knockdown of the CS biosynthetic enzymes CHST11 and CHST15 inhibited invasive activity, even in the presence of ROR1. These results suggest that CS is required to induce an ROR1-dependent, aggressive MDA-MB-231 phenotype. ROR1 signaling in MDA-MB-231 cells activated c-Jun N-terminal kinase (JNK), leading to increased invasive potential; moreover, exogenous CSs activated JNK. MDA-MB-231 cells express DKK1, a tumor suppressor factor that binds to CS, at high levels. Knockdown of DKK1 enhanced CS-stimulated tumor invasion activity of MDA-MB-231 cells, suggesting that DKK1 sequesters CS to block ROR1/JNK signaling. These results showed that CSs promotes cancer aggressiveness through the ROR1−JNK axis in MDA-MB-231 cells.
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影响因子：
7.3
作者：
Kagey MH;He X
通讯作者：
He X
N-钙粘着蛋白在乳腺癌细胞中的外源表达会诱导细胞迁移，侵袭和转移。
影响因子：
7.8
作者：
Hazan, R B;Phillips, G R;Qiao, R F;Norton, L;Aaronson, S A
通讯作者：
Aaronson, S A
影响因子：
4.8
作者：
Nadanaka, Satomi;Ishida, Miho;Kitagawa, Hiroshi
通讯作者：
Kitagawa, Hiroshi
DOI：
10.1016/j.bbagen.2018.01.002
发表时间：
2018-04-01
影响因子：
3
作者：
Nadanaka, Satomi;Kitagawa, Hiroshi
通讯作者：
Kitagawa, Hiroshi
影响因子：
5.9
作者：
Kitazawa K;Nadanaka S;Kadomatsu K;Kitagawa H
通讯作者：
Kitagawa H