BIOCHEMICAL PHARMACOLOGY
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2023
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IF 5.8
Xiaoxiang Mo,Xiaoju Shen,Xiaocheng Mo,Fei Yu,Weidan Tan,Zhihua Deng,Jingchuan He,Zhuo Luo,Zhiquan Chen,Jie Yang
Small cell lung cancer (SCLC) is the most malignant lung cancer with rapid growth and early metastasis, but still lacks effective targeted therapies to improve the prognosis. Here, we demonstrated that a novel oncogenic protein, cell migration inducing hyaluronic binding protein (CEMIP), was robustly overexpressed in SCLC tissues than that in noncancerous tissues and high expression of CEMIP predicted poor outcomes in clinical specimens and in large sample size cohorts from public databases (GEPIA 2 and CPTAC). Liquid chromatography mass spectrometry (LC-MS) and in vitro/in vivo functional assays indicated that CEMIP contributed to the proliferation by increasing glutamine consumption and their metabolites (glutamate and glutathione) levels in SCLC cells. Moreover, the addition of a GLS1 inhibitor CB-839 dramatically reduced CEMIP-induced SCLC cell proliferation . Mechanistically, beyond as a scaffold protein , CEMIP facilitates glutamine-dependent cell proliferation through inhibiting c-Myc ubiquitination and increasing c-Myc stabilization and nuclear accumulation via hindering the interaction between FBXW7 (a E3 ubiquitin ligase) and its target substrate c-Myc. Taken together, our findings reveal a novel oncogenic role of CEMIP in sustaining SCLC growth via FBXW7/c-Myc-dependent axis, and provide new evidence that inhibition of CEMIP might be a potential therapeutic strategy for the treatment of SCLC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Cancer Cell International
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2024
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IF 5.3
Boya Deng,Siyang Zhang,Yingying Zhou,Ting Sun,Ying Zhu,Jing Fei,Ailin Li,Yuan Miao
Coiled-coil domain containing 88C (CCDC88C) is a component of non-canonical Wnt signaling, and its dysregulation causes colorectal cancer metastasis. Dysregulated expression of CCDC88C was observed in lymph node metastatic tumor tissues of breast cancer. However, the role of CCDC88C in breast cancer metastasis remains unclear. To address this, the stable BT549 and SKBR3 cell lines with CCDC88C overexpression or knockdown were developed. Loss/gain-of-function experiments suggested that CCDC88C drove breast cancer cell motility in vitro and lung and liver metastasis in vivo. We found that CCDC88C led to c-JUN-induced transcription activation. Overlapping genes were identified from the genes modulated by CCDC88C and c-JUN. CEMIP , one of these overlapping genes, has been confirmed to confer breast cancer metastasis. We found that CCDC88C regulated CEMIP mRNA levels via c-JUN and it exerted pro-metastatic capabilities in a CEMIP-dependent manner. Moreover, we identified the CCDC88C as a substrate of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6). GALNT6 was positively correlated with CCDC88C protein abundance in the normal breast and breast cancer tissues, indicating that GALNT6 might be associated with expression patterns of CCDC88C in breast cancer. Our data demonstrated that GALNT6 maintained CCDC88C stability by promoting its O-linked glycosylation, and the modification was critical for the pro-metastatic potential of CCDC88C. CCDC88C also could mediate the pro-metastatic potential of GALNT6 in breast cancer. Collectively, our findings uncover that CCDC88C may increase the risk of breast cancer metastasis and elucidate the underlying molecular mechanisms. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-024-03413-2.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Zeming Lei,Yansheng Wang,Liangzi Yin,Ziyuan Wang,Lunhao Bai
Wear particle-induced periprosthetic osteolysis (PPO) represents the primary reason for implant failure following joint replacement, driven by macrophage polarization and excessive osteoclastogenesis. While cell migration inducing hyaluronidase 1 (CEMIP) has been implicated in inflammation and bone metabolism, its role in wear particle-induced PPO remains unexplored. Here, we discover that CEMIP expression was upregulated in Ti particle-induced calvarial osteolysis model. Functional studies revealed that CEMIP knockdown could attenuate Ti particle-triggered bone resorption via suppressing macrophage M1 polarization, promoting M2 polarization, and inhibiting osteoclast differentiation, as evidenced by reduced M1 markers, increased M2 markers, decreased inflammatory cytokines, and osteoclast-specific gene expression. In vitro, CEMIP silencing suppressed IFNγ-induced M1 polarization, enhanced IL-4-induced M2 polarization, and RANKL/M-CSF-triggered osteoclastogenesis in bone marrow-derived macrophages (BMDMs). Mechanistically, wear particle exposure decreases N6-methyladenosine (m6A) modification of CEMIP mRNA, impairing m6A reader protein YTH N6-methyladenosine RNA binding protein F2 (YTHDF2)-mediated recognition and subsequent mRNA decay, thereby stabilizing CEMIP transcripts and enhancing their expression. Furthermore, CEMIP knockdown counteracted the enhancement of M1 macrophage polarization and osteoclast differentiation resulting from YTHDF2 silencing. Collectively, these findings highlight the critical role of the YTHDF2/CEMIP axis in regulating macrophage polarization and osteoclast differentiation, thus offering a promising therapeutic target for wear particle-induced PPO.
研究领域:
分子生物学
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骨科
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免疫学
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骨代谢
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表观遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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