Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1.
Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1.
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DOI：
10.1158/0008-5472.can-16-0980
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发表时间：
2016-11-01
期刊：
影响因子：
11.2
通讯作者：
Wang TL
中科院分区：
文献类型：
--
作者：
Jung JG;Shih IM;Park JT;Gerry E;Kim TH;Ayhan A;Handschuh K;Davidson B;Fader AN;Selleri L;Wang TL
The evolution of chemoresistance is a fundamental characteristic of cancer that ultimately defeats its clinical management. However, it may be possible improve patient outcomes significantly by defeating nodal resistance mechanisms which cancers rely upon during the evolution to an untreatable state. Here we report an essential role for upregulation of the stem cell reprogramming factor PBX1 in mediating chemoresistance in recurrent ovarian carcinomas. In clinical specimens, high levels of PBX1 expression correlated with shorter survival in post-chemotherapy ovarian cancer patients. In tumor cells with low endogenous expression of PBX1, its enforced expression promoted cancer stem cell-like phenotypes, including most notably an increase in resistance to platinum-based therapy used most commonly for management of this disease. Conversely, silencing PBX1 in platinum-resistant cells that overexpressed PBX1 sensitized them to platinum treatment and reduced their stem-like properties. An analysis of published genome-wide chromatin immunoprecipitation data indicated that PBX1 binds directly to promoters of genes involved in stem cell maintenance and the response to tissue injury. We confirmed direct regulation of one of these genes, STAT3, demonstrating that the PBX1 binding motif at its promoter acted to positively regulate STAT3 transcription. Pursing this connection, we determined that a STAT3/JAK2 inhibitor could potently sensitize platinum-resistant cells to carboplatin and suppress their growth in vivo. Our findings offer a mechanistic rationale to target the PBX1/STAT3 axis to defeat a key mechanism of chemoresistance in ovarian cancers and possibly other human cancers.
