HOXB13 is downregulated in colorectal cancer to confer TCF4-mediated transactivation.
HOXB13 is downregulated in colorectal cancer to confer TCF4-mediated transactivation.
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DOI：
10.1038/sj.bjc.6602631
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发表时间：
2005-06-20
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
Wnt信号级联中的突变被认为通过T细胞因子-4（TCF 4）及其下游生长调节因子引起结直肠细胞的异常增殖。HOXB 13仅在前列腺和结肠直肠中表达。在前列腺癌中，HOXB 13负调节β-catenin/TCF 4介导的反式激活，随后抑制细胞生长。为了研究HOXB 13在结直肠肿瘤发生中的作用，我们采用定量RT-PCR分析法检测了53例起源于左结肠远端至直肠的结直肠肿瘤及其相应正常组织中HOXB 13的表达。HOXB 13的表达在42个有效肿瘤中的26个（62%）中丢失或减少，而TCF 4 RNA的表达与HOXB 13的表达无关。TCF 4启动子分析表明HOXB 13在转录水平上不调控TCF 4。然而，HOXB 13在蛋白水平下调TCF 4及其靶基因c-myc的表达，从而抑制β-catenin/TCF介导的信号传导。从功能上讲，HOXB 13的强制表达驱使结直肠癌（CRC）细胞生长受到抑制。这是首次描述HOXB 13在CRC中的下调，其作用机制是通过调节TCF 4蛋白的稳定性介导的。我们的研究结果表明，HOXB 13的丢失可能是结直肠细胞转化的重要事件，考虑到超过90%的结直肠肿瘤保留APC/β-catenin通路中的突变。
Mutations in the Wnt signalling cascade are believed to cause aberrant proliferation of colorectal cells through T-cell factor-4 (TCF4) and its downstream growth-modulating factors. HOXB13 is exclusively expressed in prostate and colorectum. In prostate cancers, HOXB13 negatively regulates β-catenin/TCF4-mediated transactivation and subsequently inhibits cell growth. To study the role of HOXB13 in colorectal tumorigenesis, we evaluated the expression of HOXB13 in 53 colorectal tumours originated from the distal left colon to rectum with their matching normal tissues using quantitative RT–PCR analysis. Expression of HOXB13 is either lost or diminished in 26 out of 42 valid tumours (62%), while expression of TCF4 RNA is not correlated with HOXB13 expression. TCF4 promoter analysis showed that HOXB13 does not regulate TCF4 at the transcriptional level. However, HOXB13 downregulated the expression of TCF4 and its target gene, c-myc, at the protein level and consequently inhibited β-catenin/TCF-mediated signalling. Functionally, forced expression of HOXB13 drove colorectal cancer (CRC) cells into growth suppression. This is the first description of the downregulation of HOXB13 in CRC and its mechanism of action is mediated through the regulation of TCF4 protein stability. Our results suggest that loss of HOXB13 may be an important event for colorectal cell transformation, considering that over 90% of colorectal tumours retain mutations in the APC/β-catenin pathway.
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影响因子：
2.7
作者：
Economides, KD;Zeltser, L;Capecchi, MR
通讯作者：
Capecchi, MR
影响因子：
4.8
作者：
Amir, AL;Barua, M;Balk, SP
通讯作者：
Balk, SP
影响因子：
254.7
作者：
Jemal, A;Tiwari, RC;Thun, MJ
通讯作者：
Thun, MJ
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW
影响因子：
8.4
作者：
DEVITA, G;BARBA, P;CILLO, C
通讯作者：
CILLO, C