癌蛋白 HBXIP 通过 MAPK/ERK 通路激活促进非小细胞肺癌发生。
Oncoprotein HBXIP promotes tumorigenesis through MAPK/ERK pathway activation in non-small cell lung cancer.
机构信息
Department of Breast Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
Department of Outpatient Office, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
出版信息
Cancer Biol Med. 2021 Feb 15;18(1):105-119. doi: 10.20892/j.issn.2095-3941.2020.0098.
OBJECTIVE
The oncoprotein, hepatitis B X-interacting protein (HBXIP), has been reported to play an important role in human malignancies. However, its functions in non-small cell lung cancer (NSCLC) are poorly understood. The goal of the present study was to identify the role of HBXIP in the regulation of NSCLC development.
METHODS
The level of HBXIP expression in NSCLC tissue was assessed by immunohistochemical and Western blot analyses, and its relationships with clinicopathological features and outcomes were statistically evaluated. The effects of HBXIP on NSCLC cell progression were assessed through cell viability, colony formation, and flow cytometry analyses . The mechanism by which HBXIP regulated the MAPK pathway was studied by Western blot, immunofluorescence, and immunoprecipitation assays. In addition, experiments were performed to evaluate the progression of NSCLC and ERK signaling pathway activation after HBXIP knockdown.
RESULTS
HBXIP was overexpressed in human NSCLC and was correlated with the invasiveness of NSCLC. The high expression of HBXIP in NSCLC was significantly correlated with gender ( = 0.033), N stage ( = 0.002), and tumor-node-metastasis stage ( = 0.008). experiments using an NSCLC cell line revealed that HBXIP knockdown resulted in the suppression of cell proliferation and colony formation, which was consistent with the enhanced cell cycle arrest in G1 phase. The results of a mechanistic investigation suggested that binding of HBXIP to MEK1 protein promoted MAPK/ERK signaling pathway activation in NSCLC by preventing the proteasome-mediated degradation of MEK1. In addition, the results obtained using subcutaneous tumor xenografts confirmed that HBXIP deficiency decreased MEK1 protein levels and NSCLC tumor growth.
CONCLUSIONS
Taken together, our results showed that the HBXIP-MEK interaction promoted oncogenesis the MAPK/ERK pathway, which may serve as a novel therapeutic target for cancers in which MAPK/ERK signaling is a dominant feature.
目的
乙型肝炎病毒 X 相互作用蛋白（HBXIP）是一种癌蛋白，已被报道在人类恶性肿瘤中发挥重要作用。然而，其在非小细胞肺癌（NSCLC）中的功能仍知之甚少。本研究旨在确定 HBXIP 在调节 NSCLC 发生发展中的作用。
方法
采用免疫组化和 Western blot 分析检测 NSCLC 组织中 HBXIP 的表达水平，并进行统计学分析其与临床病理特征和预后的关系。通过细胞活力、集落形成和流式细胞术分析评估 HBXIP 对 NSCLC 细胞进展的影响。采用 Western blot、免疫荧光和免疫沉淀实验研究 HBXIP 调节 MAPK 通路的机制。此外，还进行了实验以评估 HBXIP 敲低后 NSCLC 的进展和 ERK 信号通路的激活。
结果
HBXIP 在人 NSCLC 中过表达，并与 NSCLC 的侵袭性相关。HBXIP 在 NSCLC 中的高表达与性别显著相关（=0.033），与 N 分期（=0.002）和肿瘤-淋巴结-转移分期（=0.008）显著相关。使用 NSCLC 细胞系进行的实验表明，HBXIP 敲低导致细胞增殖和集落形成受到抑制，这与 G1 期细胞周期阻滞增强一致。机制研究结果表明，HBXIP 与 MEK1 蛋白结合通过防止 MEK1 的蛋白酶体介导降解促进 NSCLC 中 MAPK/ERK 信号通路的激活。此外，使用皮下肿瘤异种移植模型获得的结果证实，HBXIP 缺失降低了 MEK1 蛋白水平并抑制了 NSCLC 肿瘤生长。
结论
综上所述，我们的研究结果表明，HBXIP-MEK 相互作用促进了 MAPK/ERK 通路的致癌作用，这可能成为 MAPK/ERK 信号通路占主导特征的癌症的一种新的治疗靶点。
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