Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib.
Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib.
复制标题
DOI：
10.1038/cddis.2017.512
复制
发表时间：
2017-10-26
影响因子：
9
通讯作者：
Matter MS
中科院分区：
文献类型：
--
作者：
Quintavalle C;Hindupur SK;Quagliata L;Pallante P;Nigro C;Condorelli G;Andersen JB;Tagscherer KE;Roth W;Beguinot F;Heim MH;Ng CKY;Piscuoglio S;Matter MS
肝细胞癌（HCC）是癌症相关死亡的第三大原因，治疗选择有限，并且经常对索拉非尼（目前唯一批准用于一线治疗的药物）产生耐药性。因此，迫切需要更好地了解HCC肿瘤生物学及其对治疗的耐药性。在此，我们分析了糖尿病磷酸化蛋白（PED）在HCC中的作用。PED已被证明在几种类型的癌症中调节细胞增殖、凋亡和迁移。然而，其在HCC中的作用尚未明确。我们的研究显示，与非肿瘤组织相比，肝癌组织中PED的转录物和蛋白水平都显著高。临床病理相关性显示，ped高hcc表现出与转移和不良预后相关的基因特征富集。此外，我们还观察到，在不影响细胞增殖的情况下，PED过表达可提高肝癌细胞系的迁移潜力，而PED可抑制迁移潜力的下降。有趣的是，我们发现PED的表达受肝细胞特异性核因子HNF4α的调控。减少HNF4α诱导PED表达增加，从而促进细胞在体外的迁移。最后，PED通过抑制caspase-3/7活性降低sorafenib的抗肿瘤作用。总之，我们的数据表明PED在HCC生物学中具有重要作用。它特别作用于促进细胞迁移，并对索拉非尼治疗产生耐药性。PED可能是HCC治疗的新靶点，并可作为索拉非尼治疗反应的预测指标。
Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related death with limited treatment options and frequent resistance to sorafenib, the only drug currently approved for first-line therapy. Therefore, better understanding of HCC tumor biology and its resistance to treatment is urgently needed. Here, we analyzed the role of phosphoprotein enriched in diabetes (PED) in HCC. PED has been shown to regulate cell proliferation, apoptosis and migration in several types of cancer. However, its function in HCC has not been addressed yet. Our study revealed that both transcript and protein levels of PED were significantly high in HCC compared with non-tumoral tissue. Clinico-pathological correlation revealed that PEDhigh HCCs showed an enrichment of gene signatures associated with metastasis and poor prognosis. Further, we observed that PED overexpression elevated the migration potential and PED silencing the decreased migration potential in liver cancer cell lines without effecting cell proliferation. Interestingly, we found that PED expression was regulated by a hepatocyte specific nuclear factor, HNF4α. A reduction of HNF4α induced an increase in PED expression and consequently, promoted cell migration in vitro. Finally, PED reduced the antitumoral effect of sorafenib by inhibiting caspase-3/7 activity. In conclusion, our data suggest that PED has a prominent role in HCC biology. It acts particularly on promoting cell migration and confers resistance to sorafenib treatment. PED may be a novel target for HCC therapy and serve as a predictive marker for treatment response against sorafenib.
登录
查看更多内容
影响因子：
11.2
作者：
Bartholomeusz C;Rosen D;Wei C;Kazansky A;Yamasaki F;Takahashi T;Itamochi H;Kondo S;Liu J;Ueno NT
通讯作者：
Ueno NT
影响因子：
2.9
作者：
Mittal S;El-Serag HB
通讯作者：
El-Serag HB
PEA-15在丝氨酸104和丝氨酸116上均未磷酸化可通过阻断β-catenin抑制卵巢癌细胞的肿瘤性和进展。
影响因子：
6.2
作者：
Lee, J.;Bartholomeusz, C.;Krishnamurthy, S.;Liu, P.;Saso, H.;LaFortune, T. A.;Hortobagyi, G. N.;Ueno, N. T.
通讯作者：
Ueno, N. T.
DOI：
10.1002/cjp2.37
发表时间：
2016-04
期刊：
The journal of pathology. Clinical research
影响因子：
--
作者：
Makowska Z;Boldanova T;Adametz D;Quagliata L;Vogt JE;Dill MT;Matter MS;Roth V;Terracciano L;Heim MH
通讯作者：
Heim MH
影响因子：
5.3
作者：
Hayhurst, GP;Lee, YH;Gonzalez, FJ
通讯作者：
Gonzalez, FJ