Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
Ann Surg Oncol. 2019 Mar;26(3):836-844. doi: 10.1245/s10434-018-07149-y. Epub 2019 Jan 7.
Identification of gastric cancer-related molecules is necessary to elucidate the pathological mechanisms of this heterogeneous disease. The purpose of this study was to identify novel genes associated with aggressive phenotypes of gastric cancer.
Global expression profiling was conducted using tissues from four patients with metastatic gastric cancer to identify genes overexpressed in gastric cancer. Fifteen gastric cell lines and 262 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis. The contribution of the candidate gene on gastric cancer cell proliferation, invasion, adhesion, and migration were evaluated using small interfering RNA.
DnaJ heat shock protein family (Hsp40) member C12 (DNAJC12) was identified as a candidate gene by transcriptome analysis. In clinical samples, DNAJC12 mRNA levels were higher in gastric cancer tissues compared with normal adjacent tissues. Patients with high DNAJC12 expression showed significantly shorter overall survival in our cohort and in the extra-validation cohort analyzed by a published microarray dataset. High DNAJC12 expression in gastric cancer tissues was significantly associated with lymphatic involvement, infiltrative growth type, lymph node metastasis, and advanced stage and was identified as an independent prognostic factor for overall survival in multivariable analysis. Increased expression of DNAJC12 was found in 12 of 14 examined gastric cancer cell lines. Knockdown of DNAJC12 expression significantly decreased the proliferation and invasion abilities of gastric cancer cells.
Our findings support DNAJC12 as a candidate gene associated with aggressive phenotypes of gastric cancer.
鉴定与胃癌相关的分子对于阐明这种异质性疾病的病理机制是必要的。本研究的目的是鉴定与胃癌侵袭性表型相关的新基因。
使用来自四名转移性胃癌患者的组织进行全基因组表达谱分析，以鉴定在胃癌中过度表达的基因。对 15 种胃癌细胞系和 262 对手术切除的胃癌组织进行 mRNA 表达分析。使用小干扰 RNA 评估候选基因对胃癌细胞增殖、侵袭、黏附和迁移的贡献。
通过转录组分析鉴定出 DNAJ 热休克蛋白家族（Hsp40）成员 C12（DNAJC12）为候选基因。在临床样本中，与正常相邻组织相比，胃癌组织中的 DNAJC12 mRNA 水平更高。在我们的队列和通过已发表的微阵列数据集进行的额外验证队列中，高 DNAJC12 表达的患者总生存期明显缩短。在胃癌组织中高 DNAJC12 表达与淋巴浸润、浸润性生长类型、淋巴结转移和晚期以及多变量分析中被确定为总生存期的独立预后因素显著相关。在 14 种检查的胃癌细胞系中发现了 12 种 DNAJC12 表达增加。DNAJC12 表达的下调显著降低了胃癌细胞的增殖和侵袭能力。
我们的研究结果支持 DNAJC12 作为与胃癌侵袭性表型相关的候选基因。
