Golgi Phosphoprotein 3 Promotes Colon Cancer Cell Metastasis Through STAT3 and Integrin α3 Pathways.
Golgi Phosphoprotein 3 Promotes Colon Cancer Cell Metastasis Through STAT3 and Integrin α3 Pathways.
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DOI：
10.3389/fmolb.2022.808152
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发表时间：
2022
影响因子：
5
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Huang A;Wang R;Cui J;Gao Y;Yin Z;Chen L;He M;Li W
背景：最近有报道称，高尔基体磷蛋白3(GOLPH3)的过度表达与结直肠癌患者的临床预后不良有关。然而，GOLPH3促进结直肠癌转移的潜在分子机制仍然知之甚少。方法：采用siRNA转染法对GOLPH3进行体外基因消融，并利用慢病毒系统构建稳定高表达的GOLPH3结肠癌细胞系。细胞侵袭和迁移分析在有或没有Matrigel的情况下进行。免疫印迹、定量逆转录聚合酶链式反应、免疫荧光和免疫组织化学方法检测GOLPH3、ZEB1、整合素α3的表达水平及信号转导通路3、AKT/mTOR和Raf/MEK/ERK信号通路的磷酸化水平。用免疫共沉淀法研究GOLPH3与p-STAT3(Tyr705)或总STAT3的相互作用。结果：GOLPH3在结直肠癌组织和结肠癌细胞系中均有过表达。用siRNAs敲除GOLPH3可显著抑制HCT116和HCT8细胞的侵袭和迁移。相反，GOLPH3的过表达促进了结肠癌细胞的迁移和侵袭能力。GOLPH3基因敲除后，STAT3的磷酸化水平以及ZEB1和整合素α3的蛋白和mR NA水平显著降低。结直肠癌组织中整合素α3的表达与GOLPH3的表达呈正相关。免疫共沉淀实验表明，GOLPH3与pSTAT3(Tyr705)和总STAT3相互作用。我们进一步的实验表明，GOLPH3促进了IL-6诱导的STAT3的激活，进而诱导了整合素α3和ZEB1的转录，从而促进了结直肠癌的转移和发展。结论：GOLPH3可促进结肠癌细胞中STAT3的激活，并调节结肠癌细胞中转录因子ZEB1和整合素α3的表达。这些发现表明，GOLPH3在结直肠癌转移中起关键作用，可能成为结直肠癌治疗的新靶点。
Background: Golgi phosphoprotein 3 (GOLPH3) overexpression was recently reported to be associated with a poor clinical outcome in patients with colorectal cancer (CRC). However, the underlying molecular mechanism through which GOLPH3 promotes CRC metastasis remains poorly understood. Methods: In vitro genetic ablation of GOLPH3 was performed using siRNA transfection, and a stably overexpressed GOLPH3 colon cancer cell line was constructed using the lentivirus system. Cell invasion and migration assays were conducted with or without Matrigel. Immunoblotting, qRT-PCR, immunofluorescence and immunohistochemistry were utilized to study the expression level of GOLPH3, ZEB1, integrin α3 and phosphorylation level of STAT3, AKT/mTOR and Raf/MEK/ERK pathways. Co-immunoprecipitation was used to investigate the interaction between GOLPH3 and p-STAT3 (Tyr705) or total STAT3. Results: Overexpression of GOLPH3 was found in CRC tissues and colon cancer cell lines. Knockdown of GOLPH3 using siRNAs significantly suppressed the invasion and migration of HCT116 and HCT8 cells. In contrast, the overexpression of GOLPH3 promoted the migratory and invasive ability of colon cancer cells. The phosphorylation level of STAT3 as well as the protein and mRNA levels of ZEB1 and integrin α3, were significantly decreased after GOLPH3 knockdown. Moreover, Integrin α3 expression was correlated with GOLPH3 expression in CRC tissues. Co-immunoprecipitation assay revealed that GOLPH3 interacted with pSTAT3 (Tyr705) and total STAT3. Our further experiments suggested that GOLPH3 facilitated IL-6 induced STAT3 activation and subsequently induced transcription of integrin α3 and ZEB1, which promoted the metastasis and progression of CRC. Conclusion: Our current work demonstrates that GOLPH3 facilitates STAT3 activation and regulates the expression of EMT transcription factor ZEB1 and Integrin α3 in colon cancer cells. These findings indicate that GOLPH3 plays a critical role in CRC metastasis and might be a new therapeutic target for CRC treatment.
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影响因子：
4.8
作者：
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影响因子：
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高尔基体磷蛋白 3 (GOLPH3) 通过激活 NF-κB 通路促进肝细胞癌细胞侵袭性
影响因子：
7.3
作者：
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通讯作者：
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