Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Ann Surg Oncol. 2019 May;26(5):1535-1543. doi: 10.1245/s10434-019-07166-5. Epub 2019 Jan 23.
The detection of molecules and mechanisms affecting the malignant phenotype of gastric cancer cells may contribute to the identification of biomarkers for metastasis and recurrence, and such molecules may serve as targets of therapy. For this purpose, in this study transcriptome analysis was performed using surgically resected specimens from patients with gastric cancer with synchronous metastasis. We identified homeobox C10 (HOXC10) as the most highly expressed gene in gastric cancer tissues compared with the adjacent noncancerous gastric mucosa.
Polymerase chain reaction (PCR) array analysis was performed to identify genes coordinately expressed with HOXC10. The effects of inhibiting HOXC10 on malignant phenotype was evaluated using HOXC10 knockout gastric cancer cell lines, and antibody array analysis was performed to assess the effect of HOXC10 knockout on intracellular signaling. We used a mouse subcutaneous xenograft model to evaluate the tumorigenicity. HOXC10 expression was determined in gastric cancer tissues acquired from 300 patients with gastric cancer.
PCR array analysis revealed that the levels of HOXC10 messenger RNA positively correlated with those of FGFBP1 and SOX10. The phosphorylation of ERK1/2 was decreased in HOXC10 knockout cells. HOXC10 knockout significantly suppressed proliferation by increasing apoptosis and reducing the migration and invasiveness of gastric cancer cells. Mouse xenograft models revealed that the tumorigenicity of HOXC10 knockout cells was attenuated compared with the parental cells. The relatively high expression levels of HOXC10 in gastric cancer tissues were significantly associated with hepatic and peritoneal recurrence, as well as worse prognosis.
Our results indicated that HOXC10 enhances the malignant phenotype of gastric cancer cells. The expression levels of HOXC10 may therefore serve as a prognostic biomarker and the products of HOXC10 may provide targets of therapy.
检测影响胃癌细胞恶性表型的分子和机制可能有助于鉴定转移和复发的生物标志物，这些分子也可能成为治疗的靶点。为此，本研究采用手术切除的胃癌伴同步转移患者标本进行转录组分析。与相邻非癌性胃黏膜相比，我们发现 HOXC10（同源盒 C10）在胃癌组织中表达最高。
采用聚合酶链反应（PCR）阵列分析鉴定与 HOXC10 协同表达的基因。采用 HOXC10 敲除胃癌细胞系评估抑制 HOXC10 对恶性表型的影响，并采用抗体阵列分析评估 HOXC10 敲除对细胞内信号的影响。我们使用小鼠皮下异种移植模型来评估致瘤性。在 300 例胃癌患者的胃癌组织中检测 HOXC10 的表达。
PCR 阵列分析显示，HOXC10 信使 RNA 的水平与 FGFBP1 和 SOX10 的水平呈正相关。HOXC10 敲除细胞中 ERK1/2 的磷酸化减少。HOXC10 敲除通过增加细胞凋亡、减少胃癌细胞的迁移和侵袭，显著抑制增殖。小鼠异种移植模型显示，HOXC10 敲除细胞的致瘤性较亲本细胞减弱。胃癌组织中 HOXC10 的相对高表达水平与肝转移和腹膜转移以及较差的预后显著相关。
我们的结果表明 HOXC10 增强了胃癌细胞的恶性表型。因此，HOXC10 的表达水平可能成为一种预后生物标志物，HOXC10 的产物可能提供治疗靶点。
