分子腫瘤學5細胞信號轉(zhuǎn)導與腫瘤-閱讀頁
2024-11-02 11:51本頁面
【正文】 equent JAK activation trigger a cascade of signaling events, which control survival, proliferation and differen tiation of different cell types. During the past several years, several JAK mutations have been identified that encode constitutively active or hyperactive JAK proteins, which have crucial roles in hematopoietic malignancies, especially myeloproliferative neoplasms. When expressed in cells and bound to membrane cytokine receptors, mutant JAK proteins are no longer maintained in an inactive state, and they persistently activate STAT proteins . This activity promotes oncogenic transformation and uncontrolled blood cell production. The role of JAK–STAT mutations in cancer has only recently begun to be explored, and it is possible that mutations in ponents of this pathway are present in a wide variety of cancers. Mutations in JAKs and disease association JAKs Substitution Disease association JAK2 (human) V617F MPDs K539L (and the region F537–E543) PV T875N Acute megakaryoblastic myeloid leukemia Deletion of IREED Acute lymphoblastic leukemia (position 682–686) JAK3 (human) A572V Acute megakaryoblastic myeloid leukemia V722I Acute megakaryoblastic myeloid leukemia P132T Acute megakaryoblastic myeloid leukemia JAK1 (human) G871E Uterine leiomyosaras [45] 可能機制： STAT活化與腫瘤細胞凋亡異常： STAT3 / STAT5可通過抑制凋亡來介導細胞惡性演進； STAT3/BclxL信號通路在凋亡中發(fā)揮重要作用 STAT活化與腫瘤細胞周期異常： CyclinD1與 CDK4和 CDK6結(jié)合有助于 G1/S期進程，在 CyclinD1調(diào)控區(qū)的 481位有 STAT5的結(jié)合位點，提示 STAT5 通過介導 CyclinD1表達刺激細胞增殖導致癌變。 此外， STAT3還能調(diào)控 CDKI（如 p21等） STAT活化與腫瘤細胞侵襲與轉(zhuǎn)移 腫瘤細胞侵襲與轉(zhuǎn)移包括細胞的黏附、運動、細胞外基質(zhì)降解、 血管生成等一系列病理生理過程。 在黑色素瘤細胞中， STAT3可活化金屬蛋白酶 2（ MMP2），降解細胞外基質(zhì)。 STAT3可直接作用于其啟動子，上調(diào)其表達 STAT活化與腫瘤細胞免疫逃逸： STAT3通過促進 DC細胞的分化成熟及參與其異常分化，導致 T細胞免疫識別障礙，從而使腫瘤細胞獲得免疫耐受
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