Angiopoietin-like protein 2 renders colorectal cancer cells resistant to chemotherapy by activating spleen tyrosine kinase-phosphoinositide 3-kinase-dependent anti-apoptotic signaling.
Angiopoietin-like protein 2 renders colorectal cancer cells resistant to chemotherapy by activating spleen tyrosine kinase-phosphoinositide 3-kinase-dependent anti-apoptotic signaling.
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DOI：
10.1111/cas.12554
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发表时间：
2014-12
期刊：
影响因子：
5.7
通讯作者：
Oike Y
中科院分区：
文献类型：
--
作者：
Horiguchi H;Endo M;Miyamoto Y;Sakamoto Y;Odagiri H;Masuda T;Kadomatsu T;Tanoue H;Motokawa I;Terada K;Morioka MS;Manabe I;Baba H;Oike Y
血管生成素样蛋白2（Angiopoietin-like protein 2，ANGPTL 2）通过激活肿瘤血管生成、肿瘤细胞的趋化性和侵袭性，在炎症性肿瘤的发生和肿瘤转移中发挥重要作用。然而，目前尚不清楚ANGPTL 2表达是否对肿瘤细胞存活有影响。在这里，我们通过确定ANGPTL 2表达是否改变了用顺铂治疗的人结直肠癌细胞系的存活率来探索这种可能性。为此，我们产生了表达ANGPTL 2的SW 480细胞（SW 480/ANGPTL 2）和对照（SW 480/Ctrl）细胞。与对照细胞相比，SW 480/ANGPTL 2中由抗肿瘤药物处理诱导的凋亡显著减少。与SW 480/Ctrl细胞相比，抗凋亡BCL-2家族基因的表达在SW 480/ANGPTL 2中上调。为了评估ANGPTL 2下游的信号传导，我们对SW 480/ANGPTL 2和SW 480/Ctrl细胞进行了RNA测序分析。该分析结合体外实验表明，Syk-PI 3 K信号转导诱导了SW 480/ANGPTL 2细胞中BCL-2家族基因的表达。此外，ANGPTL 2通过激活脾酪氨酸激酶-活化T细胞核因子（Syk-NFAT）途径在反馈回路中增加其自身的表达。最后，我们观察到接受化疗的结直肠癌患者的原发性不可切除肿瘤中ANGPTL 2表达较高与客观缓解率较低之间的相关性。这些发现表明，减弱肿瘤细胞中的ANGPTL 2信号传导可以阻断肿瘤细胞对化疗的抗性。
Angiopoietin-like protein 2 (ANGPTL2) plays an important role in inflammatory carcinogenesis and tumor metastasis by activating tumor angiogenesis and tumor cell chemotaxis and invasiveness. However, it is unclear whether ANGPTL2 expression has an effect on tumor cell survival. Here, we explored that possibility by determining whether ANGPTL2 expression altered survival of human colorectal cancer cell lines treated with antineoplastic drugs. To do so, we generated SW480 cells expressing ANGPTL2 (SW480/ANGPTL2) and control (SW480/Ctrl) cells. Apoptosis induced by antineoplastic drug treatment was significantly decreased in SW480/ANGPTL2 compared to control cells. Expression of anti-apoptotic BCL-2 family genes was upregulated in SW480/ANGPTL2 compared to SW480/Ctrl cells. To assess signaling downstream of ANGPTL2 underlying this effect, we carried out RNA sequencing analysis of SW480/ANGPTL2 and SW480/Ctrl cells. That analysis, combined with in vitro experiments, indicated that Syk-PI3K signaling induced expression of BCL-2 family genes in SW480/ANGPTL2 cells. Furthermore, ANGPTL2 increased its own expression in a feedback loop by activating the spleen tyrosine kinase–nuclear factor of activated T cells (Syk–NFAT) pathway. Finally, we observed a correlation between higher ANGPTL2 expression in primary unresectable tumors from colorectal cancer patients who underwent chemotherapy with a lower objective response rate. These findings suggest that attenuating ANGPTL2 signaling in tumor cells may block tumor cell resistance to antineoplastic therapies.
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DOI：
10.1093/bioinformatics/btq033
发表时间：
2010-03-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Quinlan AR;Hall IM
通讯作者：
Hall IM
影响因子：
8.8
作者：
Nita ME;Nagawa H;Tominaga O;Tsuno N;Fujii S;Sasaki S;Fu CG;Takenoue T;Tsuruo T;Muto T
通讯作者：
Muto T
影响因子：
4.8
作者：
de Castro, Rodrigo O.;Zhang, Juan;Siraganian, Reuben P.
通讯作者：
Siraganian, Reuben P.
EMT，癌症干细胞和耐药性：癌症战争中新兴的邪恶轴。
影响因子：
8
作者：
Singh, A.;Settleman, J.
通讯作者：
Settleman, J.
影响因子：
6
作者：
Okada, Tatsuya;Tsukano, Hiroto;Oike, Yuichi
通讯作者：
Oike, Yuichi