CHA Cancer Institute, College of Life Science, CHA University, Seongnam City, Republic of Korea.
CHA Cancer Institute, College of Life Science, CHA University, Seongnam City, Republic of Korea. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan. School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Japan.
Cancer Res. 2015 Aug 1;75(15):3087-97. doi: 10.1158/0008-5472.CAN-14-3751. Epub 2015 Jun 4.
Recent advances in genome and transcriptome analysis have contributed to the identification of many potential cancer-related genes. Furthermore, biological and clinical investigations of the candidate genes provide us with a better understanding of carcinogenesis and development of cancer treatment. Here, we report a novel role of KIAA1324 as a tumor suppressor in gastric cancer. We observed that KIAA1324 was downregulated in most gastric cancers from transcriptome sequencing data and found that histone deacetylase was involved in the suppression of KIAA1324. Low KIAA1324 levels were associated with poor prognosis in gastric cancer patients. In the xenograft model, KIAA1324 significantly reduced tumor formation of gastric cancer cells and decreased development of preformed tumors. KIAA1324 also suppressed proliferation, invasion, and drug resistance and induced apoptosis in gastric cancer cells. Through protein interaction analysis, we identified GRP78 (glucose-regulated protein 78 kDa) as a KIAA1324-binding partner. KIAA1324 blocked oncogenic activities of GRP78 by inhibiting GRP78-caspase-7 interaction and suppressing GRP78-mediated AKT activation, thereby inducing apoptosis. In conclusion, our study reveals a tumor suppressive role of KIAA1324 via inhibition of GRP78 oncoprotein activities and provides new insight into the diagnosis and treatment of gastric cancer.
近年来，基因组和转录组分析的进展有助于鉴定许多潜在的癌症相关基因。此外，对候选基因的生物学和临床研究使我们更好地了解癌症的发生和发展以及癌症治疗。在这里，我们报告了 KIAA1324 作为胃癌肿瘤抑制因子的新作用。我们观察到 KIAA1324 在大多数胃癌的转录组测序数据中下调，并发现组蛋白去乙酰化酶参与了 KIAA1324 的抑制。低水平的 KIAA1324 与胃癌患者的预后不良相关。在异种移植模型中，KIAA1324 显著减少了胃癌细胞的肿瘤形成，并降低了已形成肿瘤的发展。KIAA1324 还抑制了胃癌细胞的增殖、侵袭和耐药性，并诱导其凋亡。通过蛋白相互作用分析，我们鉴定出 GRP78（葡萄糖调节蛋白 78kDa）是 KIAA1324 的结合伴侣。KIAA1324 通过抑制 GRP78-caspase-7 相互作用和抑制 GRP78 介导的 AKT 激活来阻断 GRP78 的致癌活性，从而诱导细胞凋亡。总之，我们的研究揭示了 KIAA1324 通过抑制 GRP78 癌蛋白活性发挥肿瘤抑制作用，并为胃癌的诊断和治疗提供了新的见解。
