NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer.
NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer.
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DOI：
10.1371/journal.pgen.1003552
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Grady WM
中科院分区：
文献类型：
--
作者：
Luo Y;Kaz AM;Kanngurn S;Welsch P;Morris SM;Wang J;Lutterbaugh JD;Markowitz SD;Grady WM
NTRK3是神经营养因子受体家族的一员，调节细胞存活。它似乎是一种依赖受体，因此有可能作为致癌基因或肿瘤抑制基因。NTRK3是NT-3的受体，当与NT-3结合时，它诱导细胞存活，但当NT-3游离时，它诱导细胞凋亡。我们通过对高甲基化基因的全基因组筛选，在结直肠癌中发现了异常甲基化的NTRK3。这一发现使我们评估NTRK3是否可能是结肠中的肿瘤抑制基因。NTRK3在60%的结肠腺瘤和67%的结肠腺癌中甲基化。NTRK3甲基化抑制NTRK3的表达。如果NT-3缺失，NTRK3重组可诱导结直肠癌细胞凋亡。此外，NTRK3表达的缺失与体外和体内的肿瘤转化有关。我们还发现，在人类结直肠癌中发现的自然发生的突变体NTRK3可以抑制NTRK3的抑瘤活性。综上所述，我们的研究结果表明，NTRK3是一种条件肿瘤抑制基因，在结直肠癌中通常通过表观遗传和遗传机制失活，其在结直肠癌发病中的功能取决于其配体NT-3的表达状态。NTRK3是一种神经营养因子受体，在某些组织中似乎是一种依赖性受体。NTRK3先前已被证明是乳腺癌和可能的肝细胞癌的致癌基因。通过全基因组甲基化筛选，我们意外地发现NTRK3在结直肠癌中普遍甲基化，而在正常结肠样本中却没有甲基化，这促使我们评估NTRK3是否可能是结肠中的肿瘤抑制基因。我们现在证明NTRK3在结直肠腺瘤和癌症中经常甲基化。在缺乏其配体NT-3的情况下，诱导NTRK3表达导致细胞凋亡，抑制体外非锚定集落形成和体内肿瘤生长。重新引入NT-3可以释放NTRK3介导的结肠癌细胞凋亡，这与NTRK3在结肠中的依赖性受体一致。最后，NTRK3的体细胞突变已经在原发性人类结直肠癌中被观察到。我们提供的证据表明，这些突变的一个子集使NTRK3的肿瘤抑制活性失活。这些发现表明，NTRK3是结肠中的一种条件肿瘤抑制基因，通过遗传和表观遗传机制失活，其在结直肠癌发病中的功能取决于其配体NT-3的表达状态。
NTRK3 is a member of the neurotrophin receptor family and regulates cell survival. It appears to be a dependence receptor, and thus has the potential to act as an oncogene or as a tumor suppressor gene. NTRK3 is a receptor for NT-3 and when bound to NT-3 it induces cell survival, but when NT-3 free, it induces apoptosis. We identified aberrantly methylated NTRK3 in colorectal cancers through a genome-wide screen for hypermethylated genes. This discovery led us to assess whether NTRK3 could be a tumor suppressor gene in the colon. NTRK3 is methylated in 60% of colon adenomas and 67% of colon adenocarcinomas. NTRK3 methylation suppresses NTRK3 expression. Reconstitution of NTRK3 induces apoptosis in colorectal cancers, if NT-3 is absent. Furthermore, the loss of NTRK3 expression associates with neoplastic transformation in vitro and in vivo. We also found that a naturally occurring mutant NTRK3 found in human colorectal cancer inhibits the tumor suppressor activity of NTRK3. In summary, our findings suggest NTRK3 is a conditional tumor suppressor gene that is commonly inactivated in colorectal cancer by both epigenetic and genetic mechanisms whose function in the pathogenesis of colorectal cancer depends on the expression status of its ligand, NT-3. NTRK3 is a neurotrophin receptor and appears to be a dependence receptor in certain tissues. NTRK3 has been previously shown to be an oncogene in breast cancer and possibly hepatocellular carcinoma. Through a genome-wide methylation screen, we unexpectedly found that NTRK3 is commonly methylated in colorectal cancers but not in normal colon samples, which led us to assess whether NTRK3 could be a tumor suppressor gene in the colon. We now demonstrate that NTRK3 is frequently methylated in colorectal adenomas and cancers. Induced NTRK3 expression in the absence of its ligand, NT-3, causes apoptosis and suppresses in vitro anchorage-independent colony formation and in vivo tumor growth. Reintroduction of NT-3 releases colon cancer cells from NTRK3-mediated apoptosis, which is consistent with NTRK3 being a dependence receptor in the colon. Finally, somatic mutations of NTRK3 have been observed in primary human colorectal cancer. We provide evidence that a subset of these mutations inactivate tumor suppressor activities of NTRK3. These findings suggest that NTRK3 is a conditional tumor suppressor gene in the colon that is inactivated by both genetic and epigenetic mechanisms and whose function in the pathogenesis of colorectal cancer depends on the expression status of its ligand, NT-3.
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影响因子：
78.5
作者：
Issa, JP
通讯作者：
Issa, JP
影响因子：
3.7
作者：
Kaz, Andrew M.;Wong, Chao-Jen;Grady, William M.
通讯作者：
Grady, William M.
影响因子：
50.3
作者：
Tognon, C;Knezevich, SR;Sorensen, PHB
通讯作者：
Sorensen, PHB
影响因子：
64.8
作者：
Nikoletopoulou, Vassiliki;Lickert, Heiko;Barde, Yves-Alain
通讯作者：
Barde, Yves-Alain
DOI：
10.1073/pnas.90.2.587
发表时间：
1993-01-15
影响因子：
11.1
作者：
WHITEHEAD, RH;VANEEDEN, PE;JAT, PS
通讯作者：
JAT, PS