KCTD12 is negatively regulated by Kit in gastrointestinal stromal tumors.
KCTD12 is negatively regulated by Kit in gastrointestinal stromal tumors.
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KCTD12在胃肠道肿瘤中受试剂盒负调节。
DOI：
10.18632/oncotarget.25469
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发表时间：
2018-06-05
期刊：
影响因子：
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通讯作者：
Saito T
中科院分区：
文献类型：
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作者：
Suehara Y;Akaike K;Mukaihara K;Kurisaki-Arakawa A;Kubota D;Okubo T;Mitomi H;Mitani K;Takahashi M;Toda-Ishii M;Kim Y;Tanabe Y;Takagi T;Hayashi T;Mogushi K;Kaneko K;Yao T;Saito T
我们的研究小组先前已经证明，由KCTD 12基因编码的pfetin是胃肠道间质瘤（GIST）的一个强有力的预后生物标志物。然而，控制pfetin表达的潜在机制仍然未知。为了阐明KCTD 12在GIST中的调节机制，除了KCTD 12改变和蛋白表达之间的可能关联之外，我们通过PCR直接测序检测了76例GIST患者的KCTD 12突变，并将这些结果与临床病理数据进行了比较。pfetin在GIST进展中的作用也用GIST T1细胞揭示。在该系列中，在15个病例中未观察到pfetin表达，并且pfetin表达的缺失与较高的有丝分裂率相关（>5/50 HPFs：p = 0.029）。在坏死的存在和pfetin表达的丧失之间也存在趋势，但这在统计学上不显著（p = 0.09）。KCTD 12突变在76例GIST中的22例（28.9%）中经常观察到;然而，它们不影响蛋白表达，也与患者的预后无关。KCTD 12在体外敲低导致GIST T1细胞生长加速，证实pfetin作为肿瘤抑制剂发挥作用。KIT敲除显著抑制细胞生长，并在mRNA和蛋白水平上调pfetin的表达。这些发现表明，GIST与pfetin表达的损失具有增殖优势，并在GIST中较高的pfetin表达可能是KIT的表达水平较低的指示。这种关系证实，pfetin是一个有用的预后标志物在GIST。
Our group has previously demonstrated that pfetin, encoded by the KCTD12 gene, is a strong prognostic biomarker for gastrointestinal stromal tumors (GISTs). However, the underlying mechanisms that control pfetin expression remain unknown. To elucidate the regulatory mechanisms of KCTD12 in GIST, in addition to a possible association between KCTD12 alterations and protein expression, we examined 76 patients with GISTs for KCTD12 mutations by PCR-direct sequence, and compared these results with clinicopathologic data. The function of pfetin in GIST progression was also revealed using GIST T1 cells. In this series, pfetin expression was not observed in 15 cases, and loss of pfetin expression was associated with higher mitotic rate (>5/50HPFs: p = 0.029). There was also a trend between presence of necrosis and loss of pfetin expression but this was not statistically significant (p = 0.09). KCTD12 mutations were frequently observed in 22 out of 76 GISTs (28.9%); however, they did not affect protein expression and were not associated with patients’ prognosis. KCTD12 in vitro knockdown resulted in the accelerated growth of GIST T1 cells, confirming that pfetin functions as a tumor suppressor. KIT knockdown significantly inhibited cellular growth and upregulated the expression of pfetin at both the mRNA and protein level. These findings suggest that GISTs with loss of pfetin expression has proliferative advantage and that higher pfetin expression in GISTs may be indicative of lower expression levels of KIT. This relationship confirms that pfetin is a useful prognostic marker in GISTs.