Tsai Cheng-Fang, Chen Jia-Hong, Wu Chen-Teng, Chang Pei-Chun, Wang Shu-Lin, Yeh Wei-Lan
Department of Biotechnology, Asia University, Taichung, China.
Department of General Surgery, Buddhist Tzu Chi Medical Foundation, Taichung, China.
Ther Adv Med Oncol. 2019 May 14;11:1758835919846806. doi: 10.1177/1758835919846806. eCollection 2019.
Leptin is considered a tumorigenic adipokine, suggested to promote tumorigenesis and progression in many cancers. On the other hand, intercellular adhesion molecule-1 (ICAM-1) shows altered expression in a variety of benign and malignant diseases. Histologically, ICAM-1 expression is reported as proportional to cancer stage and considered as a potential diagnosis biomarker. The altered expressions of ICAM-1 and its soluble form in malignant diseases have gained interests in recent years.
The expression of ICAM-1 and its regulatory signaling were examined by Western blot or flow cytometry. The effect of soluble ICAM-1 on osteoclast formation was investigated by tartrate-resistance acid phosphatase staining of RAW cells and tumor-induced osteolysis .
In our study, we found that leptin enhanced soluble ICAM-1 production but not surface ICAM-1 expression in lung and breast cancer cells, and this effect was regulated through leptin receptor (ObR), while silencing ObR abrogated leptin-induced soluble ICAM-1 expression. In addition, we revealed that leptin administration provoked the JAK1/2, STAT3, FAK, ERK, and GSK3αβ signaling cascade, leading to the elevation of ICAM-1 expression. Moreover, soluble ICAM-1 secreted by leptin-stimulated cancer cells synergize with the receptor activator of nuclear factor kappa-B ligand (RANKL) in inducing osteoclast formation. Soluble ICAM also enhanced tumor-induced osteolysis .
These findings suggest that soluble ICAM-1 produced under leptin treatment enhances osteoclast formation and is involved in tumor-induced osteolysis.Leptin plays an important role in physiology in health and diseases. Leptin affects immune responses that may induce inflammation and carcinogenesis. Leptin is also considered as a tumorigenic adipokine suggested to promote tumorigenesis and progression in many cancers. On the other hand, intercellular adhesion molecule-1 (ICAM-1) shows altered expression in a variety of benign and malignant diseases. Histologically, ICAM-1 expression is reported to be proportional to cancer stage and considered as a potential diagnosis biomarker. It has been reported that soluble ICAM-1 allows tumor cells to escape from immune recognition and stimulates angiogenesis and tumor growth. The altered expressions of ICAM-1 and its soluble form in malignant diseases have gained interests in recent years. In our study, we found that leptin enhanced soluble ICAM-1 production but not surface ICAM-1 expression in lung and breast cancer cells, and this effect was regulated through leptin receptor (ObR), while silencing ObR abrogated leptin-induced soluble ICAM-1 expression. In addition, we revealed that leptin administration provoked the JAK1/2, STAT3, FAK, ERK, and GSK3αβ signaling cascade, leading to the elevation of ICAM-1 expression. Moreover, soluble ICAM-1 secreted by leptin-stimulated cancer cells synergize with receptor activator of nuclear factor-kappa B ligand in inducing osteoclast formation. Soluble ICAM also enhanced tumor-induced osteolysis . These findings suggest that soluble ICAM-1 produced under leptin treatment is possibly involved in lung and breast cancer bone metastasis.
瘦素被认为是一种促肿瘤生成的脂肪因子，提示其在多种癌症中促进肿瘤发生和进展。另一方面，细胞间黏附分子-1（ICAM-1）在多种良性和恶性疾病中表达改变。组织学上，ICAM-1的表达据报道与癌症分期成正比，并被视为一种潜在的诊断生物标志物。近年来，ICAM-1及其可溶性形式在恶性疾病中的表达改变引起了关注。
通过蛋白质免疫印迹法或流式细胞术检测ICAM-1及其调节信号的表达。通过对RAW细胞进行抗酒石酸酸性磷酸酶染色以及肿瘤诱导的骨溶解来研究可溶性ICAM-1对破骨细胞形成的影响。
在我们的研究中，我们发现瘦素增强了肺癌和乳腺癌细胞中可溶性ICAM-1的产生，但不影响表面ICAM-1的表达，并且这种作用是通过瘦素受体（ObR）调节的，而沉默ObR可消除瘦素诱导的可溶性ICAM-1表达。此外，我们发现给予瘦素会引发JAK1/2、STAT3、FAK、ERK和GSK3αβ信号级联反应，导致ICAM-1表达升高。此外，瘦素刺激的癌细胞分泌的可溶性ICAM-1与核因子κB受体激活剂配体（RANKL）协同诱导破骨细胞形成。可溶性ICAM还增强了肿瘤诱导的骨溶解。
这些发现表明，瘦素处理下产生的可溶性ICAM-1增强了破骨细胞形成，并参与了肿瘤诱导的骨溶解。瘦素在健康和疾病的生理过程中起着重要作用。瘦素影响可能诱导炎症和致癌作用的免疫反应。瘦素也被认为是一种促肿瘤生成的脂肪因子，提示其在多种癌症中促进肿瘤发生和进展。另一方面，细胞间黏附分子-1（ICAM-1）在多种良性和恶性疾病中表达改变。组织学上，ICAM-1的表达据报道与癌症分期成正比，并被视为一种潜在的诊断生物标志物。据报道，可溶性ICAM-1使肿瘤细胞能够逃避免疫识别，并刺激血管生成和肿瘤生长。近年来，ICAM-1及其可溶性形式在恶性疾病中的表达改变引起了关注。在我们的研究中，我们发现瘦素增强了肺癌和乳腺癌细胞中可溶性ICAM-1的产生，但不影响表面ICAM-1的表达，并且这种作用是通过瘦素受体（ObR）调节的，而沉默ObR可消除瘦素诱导的可溶性ICAM-1表达。此外，我们发现给予瘦素会引发JAK1/2、STAT3、FAK、ERK和GSK3αβ信号级联反应，导致ICAM-1表达升高。此外，瘦素刺激的癌细胞分泌的可溶性ICAM-1与核因子κB受体激活剂配体协同诱导破骨细胞形成。可溶性ICAM还增强了肿瘤诱导的骨溶解。这些发现表明，瘦素处理下产生的可溶性ICAM-1可能参与肺癌和乳腺癌的骨转移。
