Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma.
Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma.
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KLHDC4 的上调预示着人类鼻咽癌的不良预后。
DOI：
10.1371/journal.pone.0152820
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Feng L
中科院分区：
文献类型：
--
作者：
Lian YF;Yuan J;Cui Q;Feng QS;Xu M;Bei JX;Zeng YX;Feng L
Kelch蛋白与包括癌症在内的许多人类疾病的发病机制有关。鼻咽癌在大多数国家是一种罕见的恶性肿瘤，但在中国南部和东南亚某些地区很常见。在这项研究中，我们确定了Kelch重复超家族的孤儿成员Kelch Domain Containing 4 （KLHDC4）作为鼻咽癌的预后标记。我们通过免疫组织化学染色检测了168例鼻咽癌病例中KLHDC4的表达，发现与邻近正常鼻咽黏膜相比，鼻咽癌活检组织中KLHDC4的表达水平明显较高。KLHDC4表达水平与鼻咽癌T分型（P <0.05）、N分型（P <0.05）及总分期（P <0.01）有显著相关性，且KLHDC4表达水平高的患者总体生存率（P <0.01）及无转移生存率（P <0.05）较低。通过CRISPR/ cas9介导的基因编辑敲除鼻鼻癌细胞系中的KLHDC4，可显著抑制裸鼠细胞增殖、软琼脂集落形成和肿瘤形成。此外，伤口愈合和Transwell实验显示，KLHDC4缺失也会损害细胞的迁移和侵袭。机械上，KLHDC4的缺失显著诱导鼻咽癌细胞的自发凋亡，这可以通过裂解caspase-3和裂解PARP水平的增加来证明。与此一致的是，KLHDC4敲除细胞衍生的异种移植物也显示出裂解的caspase-3和PARP升高，但Ki-67染色降低。总之，我们的研究结果表明KLHDC4通过抑制细胞凋亡促进鼻咽癌的发生。因此，KLHDC4可能作为鼻咽癌的预后生物标志物和潜在的治疗靶点。
Kelch proteins are implicated in the pathogenesis of many human diseases, including cancer. Nasopharyngeal carcinoma (NPC) is a rare malignancy in most countries, but prevalent in southern China and certain areas of Southeast Asia. In this study, we identified Kelch Domain Containing 4 (KLHDC4), an orphan member of the kelch repeat superfamily, as a prognosis marker for NPC. We examined the expression of KLHDC4 in 168 NPC cases by immunohistochemical staining and found a substantially higher level of KLHDC4 in NPC biopsies compared to adjacent normal nasopharyngeal mucosa. KLHDC4 expression was significantly related to the T classification (P <0.05), N classification (P <0.05) and total staging (P <0.01) in NPC, and patients with higher KLHDC4 expression had poorer overall (P <0.01) and metastasis-free survival (P <0.05) rates. Knockout (KO) of KLHDC4 via CRISPR/Cas9-mediated gene editing in NPC cell line dramatically inhibited cell proliferation, colony formation in soft agar and tumor formation in nude mice. In addition, cell migration and invasion were also impaired by KLHDC4 depletion as revealed by wound healing and Transwell assay. Mechanically, loss of KLHDC4 markedly induced spontaneous apoptosis in NPC cells, as evidenced by increased levels of cleaved caspase-3 and cleaved PARP. Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining. In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC.