Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer.
Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer.
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作者：
Bikkavilli RK;Avasarala S;Van Scoyk M;Arcaroli J;Brzezinski C;Zhang W;Edwards MG;Rathinam MK;Zhou T;Tauler J;Borowicz S;Lussier YA;Parr BA;Cool CD;Winn RA
细胞衰老是致癌的最初障碍。然而，触发细胞衰老的信号传导机制尚未完全理解，特别是在体内。在这里，我们确定Wnt 7a作为一种新的上游诱导细胞衰老。在两种不同的小鼠品系（C57 Bl/6 J和FVB/NJ）中，我们表明Wnt 7a的丢失是由于细胞衰老减少而导致的肺肿瘤发生增加的主要因素，而不是细胞凋亡或自噬减少。在从头条件下和两种品系中的Wnt 7a缺失小鼠显示E-钙粘蛋白到-N-钙粘蛋白转换，细胞衰老标记物的表达减少和衰老相关分泌表型的表达减少，表明这些小鼠的遗传倾向增加致癌物诱导的肺肿瘤发生。有趣的是，Wnt 7a诱导了一种替代的衰老途径，该途径不依赖于β-catenin，并且不同于由众所周知的p16 INK 4a和p19 ARF途径介导的经典癌基因诱导的衰老。从机制上讲，Wnt 7a通过S期激酶相关蛋白2（细胞衰老的重要替代调节因子）的失活诱导细胞衰老。此外，我们确定了伊洛前列素，前列环素类似物，启动下游信号级联类似于Wnt 7a，作为一种新的诱导细胞衰老，提出了潜在的未来临床翻译策略。因此，使用Wnt 7a或其模拟物伊洛前列素的促衰老疗法可能代表了肺癌的一类新的治疗方法。
Cellular senescence is an initial barrier for carcinogenesis. However, the signaling mechanisms that trigger cellular senescence are incompletely understood, particularly in vivo. Here we identify Wnt7a as a novel upstream inducer of cellular senescence. In two different mouse strains (C57Bl/6J and FVB/NJ), we show that the loss of Wnt7a is a major contributing factor for increased lung tumorigenesis owing to reduced cellular senescence, and not reduced apoptosis, or autophagy. Wnt7a-null mice under de novo conditions and in both the strains display E-cadherin-to-N-cadherin switch, reduced expression of cellular senescence markers and reduced expression of senescence-associated secretory phenotype, indicating a genetic predisposition of these mice to increased carcinogen-induced lung tumorigenesis. Interestingly, Wnt7a induced an alternate senescence pathway, which was independent of β-catenin, and distinct from that of classical oncogene-induced senescence mediated by the well-known p16INK4a and p19ARF pathways. Mechanistically, Wnt7a induced cellular senescence via inactivation of S-phase kinase-associated protein 2, an important alternate regulator of cellular senescence. Additionally, we identified Iloprost, a prostacyclin analog, which initiates downstream signaling cascades similar to that of Wnt7a, as a novel inducer of cellular senescence, presenting potential future clinical translational strategies. Thus pro-senescence therapies using either Wnt7a or its mimic, Iloprost, might represent a new class of therapeutic treatments for lung cancer.