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沉默 COPB2 通过抑制 RTK 信号通路抑制胃癌细胞的增殖并诱导细胞凋亡。

Silencing of COPB2 inhibits the proliferation of gastric cancer cells and induces apoptosis via suppression of the RTK signaling pathway.

机构信息

Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China.

Department of Clinical Laboratory Diagnosis, School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, P.R. China.

出版信息

Int J Oncol. 2019 Apr;54(4):1195-1208. doi: 10.3892/ijo.2019.4717. Epub 2019 Feb 18.

Abstract

Emerging studies have reported that coatomer protein complex subunit β2 (COPB2) is overexpressed in several types of malignant tumor; however, to the best of our knowledge, no studies regarding COPB2 in gastric cancer have been published thus far. Therefore, the present study aimed to determine the significance and function of COPB2 in gastric cancer. COPB2 expression in gastric cancer cell lines was measured using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis. In addition, lentivirus‑short hairpin RNA (shRNA) COPB2 (Lv‑shCOPB2) was generated and used to infect BGC‑823 cells to analyze the effects of COPB2 on the cancerous phenotype. The effects of shRNA‑mediated COPB2 knockdown on cell proliferation were detected using MTT, 5‑bromo‑2‑deoxyuridine and colony formation assays. In addition, the effects of COPB2 knockdown on apoptosis were analyzed by flow cytometry. Nude mice and fluorescence imaging were used to characterize the regulation of tumor growth in vivo, and qPCR and immunohistochemistry were subsequently conducted to analyze COPB2 expression in xenograft tumor tissues. Furthermore, a receptor tyrosine kinase (RTK) signaling pathway antibody array was used to explore the relevant molecular mechanisms underlying the effects of COPB2 knockdown. The results revealed that COPB2 mRNA was abundantly overexpressed in gastric cancer cell lines, whereas knockdown of COPB2 significantly inhibited cell growth and colony formation ability, and led to increased cell apoptosis in vitro. The tumorigenicity assay revealed that knockdown of COPB2 reduced tumor growth in nude mice, and fluorescence imaging indicated that the total radiant efficiency of mice in the Lv‑shCOPB2‑infected group was markedly reduced compared with the mice in the Lv‑shRNA control‑infected group in vivo. The antibody array assay revealed that the levels of phosphorylation in 23 target RTKs were significantly reduced: In conclusion, COPB2 was highly expressed in gastric cancer cell lines, and knockdown suppressed colony formation and promoted cell apoptosis via inhibiting the RTK signaling and its downstream signaling cascade molecules. Therefore, COPB2 may present a valuable target for gene silencing strategy in gastric cancer.

摘要

新兴研究报告称,衣壳蛋白复合体亚基β2(COPB2)在几种类型的恶性肿瘤中过表达;然而,据我们所知,目前尚未有关于胃癌中 COPB2 的研究。因此,本研究旨在确定 COPB2 在胃癌中的意义和功能。通过逆转录-定量聚合酶链反应(RT-qPCR)分析检测胃癌细胞系中 COPB2 的表达。此外,生成慢病毒短发夹 RNA(shRNA)COPB2(Lv-shCOPB2)并用于感染 BGC-823 细胞,以分析 COPB2 对癌细胞表型的影响。通过 MTT、5-溴-2-脱氧尿嘧啶和集落形成测定检测 shRNA 介导的 COPB2 敲低对细胞增殖的影响。此外,通过流式细胞术分析 COPB2 敲低对细胞凋亡的影响。使用裸鼠和荧光成像来描述体内肿瘤生长的调节,随后进行 qPCR 和免疫组织化学分析以分析异种移植肿瘤组织中的 COPB2 表达。此外,使用受体酪氨酸激酶(RTK)信号通路抗体阵列来探索 COPB2 敲低影响的相关分子机制。结果表明,COPB2 mRNA 在胃癌细胞系中大量过表达,而 COPB2 敲低显著抑制细胞生长和集落形成能力,并导致体外细胞凋亡增加。肿瘤发生测定表明,COPB2 敲低减少了裸鼠肿瘤的生长,荧光成像表明,与 Lv-shRNA 对照感染组的小鼠相比,Lv-shCOPB2 感染组的小鼠总辐射效率明显降低。抗体阵列分析显示,23 个靶 RTK 的磷酸化水平显著降低:总之,COPB2 在胃癌细胞系中高表达,敲低通过抑制 RTK 信号及其下游信号级联分子来抑制集落形成并促进细胞凋亡。因此,COPB2 可能成为胃癌基因沉默策略的有价值靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d7a/6411345/d8f6332d1d64/IJO-54-04-1195-g00.jpg

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