Authors' Affiliations: Departments of Pathology and Brain Korea 21 Projects for Medical Science, Yonsei University College of Medicine; and Department of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul, South Korea.
Clin Cancer Res. 2013 Sep 15;19(18):4961-71. doi: 10.1158/1078-0432.CCR-13-0131. Epub 2013 Jul 23.
Abnormal signaling through receptor tyrosine kinase (RTK) moieties is important in tumorigenesis and drug targeting of colorectal cancers. Wild-type KIT (WT-KIT), a RTK that is activated upon binding with stem cell factor (SCF), is highly expressed in some colon cancers; however, little is known about the functional role of SCF-dependent KIT activation in colon cancer pathogenesis. We aimed to elucidate the conditions and roles of WT-KIT activation in colon cancer tumorigenesis.
Colorectal cancers with KIT expression were characterized by immunoblotting and immunohistochemistry. The biologic alterations after KIT-SCF binding were analyzed with or without protein kinase C (PKC) activation.
We found that WT-KIT was expressed in a subset of colon cancer cell lines and was activated by SCF, leading to activation of downstream AKT and extracellular signal-regulated kinase (ERK) signaling pathways. We also showed that KIT expression gradually decreased, after prolonged SCF stimulation, due to lysosomal degradation. Degradation of WT-KIT after SCF binding was significantly rescued when PKC was activated. We also showed the involvement of activated PKC-δ in the recycling of WT-KIT. We further showed that a subset of colorectal cancers exhibit expressions of both WT-KIT and activated PKC-δ and that expression of KIT is correlated with poor patient survival (P = 0.004).
Continuous downstream signal activation after KIT-SCF binding is accomplished through PKC-δ-mediated recycling of KIT. This sustained KIT activation may contribute to tumor progression in a subset of colon cancers with KIT expression and might provide the rationale for a therapeutic approach targeting KIT.
受体酪氨酸激酶（RTK）部分的异常信号在肿瘤发生和结直肠癌的药物靶向中很重要。野生型 KIT（WT-KIT）是一种与干细胞因子（SCF）结合后被激活的 RTK，在一些结肠癌中高度表达；然而，关于 SCF 依赖性 KIT 激活在结肠癌发病机制中的功能作用知之甚少。我们旨在阐明 WT-KIT 激活在结肠癌发生中的条件和作用。
通过免疫印迹和免疫组织化学分析表达 KIT 的结直肠癌。分析 KIT-SCF 结合后生物变化，有无蛋白激酶 C（PKC）激活。
我们发现 WT-KIT 在一组结肠癌细胞系中表达，并被 SCF 激活，导致下游 AKT 和细胞外信号调节激酶（ERK）信号通路的激活。我们还表明，由于溶酶体降解，在长时间 SCF 刺激后，KIT 表达逐渐减少。当 PKC 被激活时，SCF 结合后 WT-KIT 的降解明显得到挽救。我们还表明激活的 PKC-δ 参与了 WT-KIT 的再循环。我们进一步表明，一部分结直肠癌表现出 WT-KIT 和激活的 PKC-δ 的表达，并且 KIT 的表达与患者生存不良相关（P = 0.004）。
KIT-SCF 结合后持续的下游信号激活是通过 PKC-δ 介导的 KIT 再循环完成的。这种持续的 KIT 激活可能有助于表达 KIT 的一部分结肠癌的肿瘤进展，并为靶向 KIT 的治疗方法提供了依据。
