Fyn requires HnRNPA2B1 and Sam68 to synergistically regulate apoptosis in pancreatic cancer
Fyn requires HnRNPA2B1 and Sam68 to synergistically regulate apoptosis in pancreatic cancer
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Fyn 需要 HnRNPA2B1 和 Sam68 协同调节胰腺癌细胞凋亡
DOI：
10.1093/carcin/bgr088
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发表时间：
2011-10-01
期刊：
影响因子：
4.7
通讯作者：
Li, Xiao-Wu
中科院分区：
文献类型：
--
作者：
Chen, Zhi-Yu;Cai, Lei;Li, Xiao-Wu
目的。Src家族激酶Fyn、异质核核糖核蛋白（HnRNP） A2B1和Sam68被认为与肿瘤转移有关，但它们在调节细胞凋亡中的作用尚不清楚。本研究探讨了Fyn在胰腺癌细胞凋亡调控中的作用及其与HnRNPA2B1和Sam68的潜在关系。实验设计。我们检测了Fyn活性和HnRNPA2B1在人胰腺癌组织中的表达，并采用多种实验方法系统地研究了Fyn活性诱导胰腺癌细胞凋亡的机制。我们发现Fyn活性在转移性胰腺癌组织中增加。在胰腺癌BxPc3细胞系中，激酶死亡的Fyn抑制Fyn活性可下调HnRNPA2B1的表达。进一步分析显示HnRNPA2B1表达与胰腺癌进展相关。在BxPc3细胞中，HnRNPA2B1与Bcl-x信使RNA （mRNA）结合，影响剪接，从而影响Bcl-x(s)的形成。通过RNA干扰（RNAi）下调HnRNPA2B1导致促凋亡的Bcl-x(s)的形成增加，促进BxPc3细胞的凋亡。此外，Fyn在BxPc3细胞中的失活降低了Sam68的磷酸化。这导致Sam68与Bcl-x mRNA结合增加，促进抗凋亡Bcl-x(L)的形成。RNAi敲低Sam68也增加了Bcl-x(L)的形成。最后，HnRNPA2B1过表达或Sam68敲低均可挽救胰腺癌细胞凋亡。我们的研究结果提示Fyn需要HnRNPA2B1和Sam68来协调和调节细胞凋亡，从而促进胰腺癌的增殖和转移。
Purpose. The Src family kinase Fyn, heterogenous nuclear ribonucleoprotein (HnRNP) A2B1 and Sam68 are thought to be associated with the metastasis of tumors, but their roles in the regulation of apoptosis remain unclear. This study investigated the role of Fyn and its potential relationship with HnRNPA2B1 and Sam68 in the regulation of apoptosis in pancreatic cancer.Experimental design. We examined both the activity of Fyn and the expression of HnRNPA2B1 in human pancreatic cancer tissues and systematically investigated the apoptotic mechanisms induced by Fyn activity using multiple experimental approaches.Results. We found that Fyn activity was increased in metastatic pancreatic cancer tissues. In the pancreatic cancer BxPc3 cell line, the inhibition of Fyn activity by kinase-dead Fyn downregulated HnRNPA2B1 expression. Further analysis showed that HnRNPA2B1 expression was associated with pancreatic cancer progression. In BxPc3 cells, HnRNPA2B1 bound to Bcl-x messenger RNA (mRNA), which affected splicing and therefore, the formation of Bcl-x(s). Downregulation of HnRNPA2B1 by RNA interference (RNAi) resulted in the increased formation of the pro-apoptotic Bcl-x(s) and promoted apoptosis of BxPc3 cells. In addition, deactivation of Fyn in BxPc3 cells reduced Sam68 phosphorylation. This resulted in increased binding between Sam68 and Bcl-x mRNA, promoting the formation of the anti-apoptotic Bcl-x(L). The knockdown of Sam68 by RNAi also increased the formation of Bcl-x(L). Finally, HnRNPA2B1 overexpression or Sam68 knockdown could rescue pancreatic cancer cells from apoptosis.Conclusion. Our results suggest a mechanism by which Fyn requires HnRNPA2B1 and Sam68 to coordinate and regulate apoptosis, thus promoting the proliferation and metastasis of pancreatic cancer.