Tao Yun, Messer Jeannette S, Goss Kathleen H, Hart John, Bissonnette Marc, Chang Eugene B
Department of Surgery and.
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Carcinogenesis. 2016 Jul;37(7):731-739. doi: 10.1093/carcin/bgw056. Epub 2016 May 4.
Colorectal cancer (CRC) develops from colonic epithelial cells that lose expression of key tumor suppressor genes and/or gain expression of proproliferative and antiapoptotic genes like heat shock protein 70 (Hsp70). Heat shock protein 70 is overexpressed in CRC, but it is not known whether this is in response to the proteotoxic stress induced by transformation, or if it contributes to the process of transformation itself. Here, using the Apc (Min/+) mouse model of CRC, we show that Hsp70 regulates mitogenic signaling in intestinal epithelial cells through stabilization of proteins involved in the receptor tyrosine kinase (RTK) and WNT signaling pathways. Loss of Hsp70 reduced tumor size with decreased proliferation and increased tumor cell death. Hsp70 loss also led to decreased expression of ErbB2, Akt, ERK and β-catenin along with decreased β-catenin transcriptional activity as measured by c-myc and axin2 expression. Upregulation of RTK or WNT signals are frequent oncogenic events in CRC and many other cancers. Thus, in addition to the role of Hsp70 in cell-survival after transformation, Hsp70 stabilization of β-catenin, Akt, ERK and ErbB2 are predicted to contribute to transformation. This has important implications not only for understanding the pathophysiology of these cancers, but also for treatment since anti-EGFR antibodies are in clinical use for CRC and EGFR is a major ErbB2 heterodimeric partner. Targeting Hsp70, therefore, might provide an alternative or complementary strategy for achieving better outcomes for CRC and other related cancer types.
结直肠癌（CRC）由结肠上皮细胞发展而来，这些细胞失去关键肿瘤抑制基因的表达和/或获得促增殖及抗凋亡基因如热休克蛋白70（Hsp70）的表达。热休克蛋白70在结直肠癌中过度表达，但尚不清楚这是对转化诱导的蛋白毒性应激的反应，还是其本身有助于转化过程。在这里，我们使用结直肠癌的Apc（Min/+）小鼠模型，表明Hsp70通过稳定参与受体酪氨酸激酶（RTK）和WNT信号通路的蛋白质来调节肠上皮细胞中的促有丝分裂信号。Hsp70的缺失减小了肿瘤大小，同时增殖减少且肿瘤细胞死亡增加。Hsp70的缺失还导致ErbB2、Akt、ERK和β-连环蛋白的表达降低，以及通过c-myc和axin2表达测量的β-连环蛋白转录活性降低。RTK或WNT信号的上调是结直肠癌和许多其他癌症中常见的致癌事件。因此，除了Hsp70在转化后细胞存活中的作用外，Hsp70对β-连环蛋白、Akt、ERK和ErbB2的稳定作用预计有助于转化。这不仅对理解这些癌症的病理生理学具有重要意义，而且对治疗也具有重要意义，因为抗EGFR抗体已在临床上用于结直肠癌治疗，且EGFR是主要的ErbB2异二聚体伴侣。因此，靶向Hsp70可能为结直肠癌和其他相关癌症类型实现更好的治疗效果提供一种替代或补充策略。
