SALL4 as an Epithelial-Mesenchymal Transition and Drug Resistance Inducer through the Regulation of c-Myc in Endometrial Cancer.
SALL4 as an Epithelial-Mesenchymal Transition and Drug Resistance Inducer through the Regulation of c-Myc in Endometrial Cancer.
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DOI：
10.1371/journal.pone.0138515
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Xi X
中科院分区：
文献类型：
--
作者：
Liu L;Zhang J;Yang X;Fang C;Xu H;Xi X
SALL 4在许多癌症的发生和发展中起重要作用。然而，SALL 4在子宫内膜癌中的作用和分子机制仍然是未知的。在本研究中，我们已经证明SALL 4在子宫内膜癌中的表达上调，并且与肿瘤分期、转移和患者的不良生存率呈正相关。SALL 4的过表达促进了子宫内膜癌细胞的侵袭性，如间充质细胞标记物N-钙粘蛋白的上调和上皮标记物E-钙粘蛋白的下调以及体外侵袭测定所示。此外，由于ATP结合盒多药转运蛋白ABCB 1表达的上调，这些细胞模型的耐药性也有所增加。此外，我们还发现ABCB 1在SALL 4诱导的耐药性中起关键作用。相反，SALL 4敲低恢复药物敏感性，逆转EMT，减少细胞转移，抑制E-钙粘蛋白的下调和N-钙粘蛋白和ABCB 1的上调。此外，ChIP检测发现，SALL 4上调c-Myc表达，c-Myc是SALL 4的直接靶点，siRNA去除c-Myc后，SALL 4下调E-cadherin表达，上调N-cadherin和ABCB 1表达，提示c-Myc是SALL 4的下游靶点，是SALL 4诱导子宫内膜癌细胞EMT、侵袭和耐药的重要机制。这些结果表明，SALL 4可能通过调控c-Myc的表达而诱导EMT和对化疗药物的耐药。SALL 4和c-Myc可能是子宫内膜癌治疗的新靶点。
SALL4 plays important roles in the development and progression of many cancers. However, the role and molecular mechanism of SALL4 in endometrial cancer remain elusive. In the present research, we have demonstrated that the expression of SALL4 was upregulated in endometrial cancer and correlated positively with tumor stage, metastases and poor survival of patients. The overexpression of SALL4 promoted the invasiveness in endometrial cancer cells, as indicated by the upregulation of mesenchymal cell marker N-cadherin and downregulation of the epithelial marker E-cadherin, and invasion assays in vitro. Additionally, there was also an increase in drug resistance in these cell models due to the upregulation of ATP-binding cassette multidrug transporter ABCB1 expression. Moreover, we also found that ABCB1 was critical for SALL4-induced drug resistance. In contrast, SALL4 knockdown restored drug sensitivity, reversed EMT, diminished cell metastasis and suppressed the downregulation of E-cadherin and the upregulation of N-cadherin and ABCB1. Furthermore, we showed that SALL4 upregulated c-Myc expression and c-Myc was a direct target for SALL4 by ChIP assay, depletion of c-Myc with siRNA abolished the SALL4-induced downregulation of E-cadherin, upregulation of N-cadherin and ABCB1, suggesting that c-Myc was a downstream target for SALL4 and required for SALL4-induced EMT, invasion and drugs resistance in endometrial cancer cells. These results indicated that SALL4 could induce EMT and resistance to antineoplastic drugs through the regulation of c-Myc. SALL4 and c-Myc may be novel therapeutic targets for endometrial cancer.