Mice deficient for the gap junction protein Connexin32 exhibit increased radiation-induced tumorigenesis associated with elevated mitogen-activated protein kinase (p44/Erk1, p42/Erk2) activation
Mice deficient for the gap junction protein Connexin32 exhibit increased radiation-induced tumorigenesis associated with elevated mitogen-activated protein kinase (p44/Erk1, p42/Erk2) activation
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DOI：
10.1093/carcin/bgh071
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发表时间：
2004-05-01
期刊：
影响因子：
4.7
通讯作者：
Lampe, PD
中科院分区：
文献类型：
--
作者：
King, TJ;Lampe, PD
连接蛋白表达/间隙连接细胞间通讯（GJIC）的缺失与生长控制下降和肿瘤发生增加有关。利用Connexin32 （Cx32）缺陷敲除小鼠的研究表明，Cx32缺失会增加化学诱导的肝肿瘤发生的易感性。在这里，除了显著增加肝脏肿瘤发生外，我们还表明，与野生型小鼠相比，利用x射线诱导肿瘤导致cx32缺陷小鼠的总体肿瘤负荷显著增加，即使排除常见的肝脏肿瘤，也会导致其他几种组织（肺、肾上腺、淋巴和小肠）的肿瘤发生。受辐射的Cx32缺陷小鼠对肝脏肿瘤发生特别敏感（46%的发生率与野生型小鼠的18%相比，P = 0.007），这表明Cx32在辐射相关突变事件中作为肝脏肿瘤抑制因子发挥作用。与野生型小鼠相比，cx32缺陷小鼠也表现出增加的肺肿瘤发生（细支气管肺泡），并增加了向癌的进展。两只缺乏cx32的小鼠发生了一种罕见的侵袭性肾上腺髓质肿瘤（嗜铬细胞瘤），在辐照野生型小鼠中未观察到。免疫组织化学分析显示，与野生型相比，cx32缺陷小鼠肝肿瘤（P = 0.006）、肺肿瘤（P = 0.056）和肾上腺肿瘤（原发性和转移性）中活化的丝裂原活化蛋白激酶（MAPK） （p44/Erk1, p42/Erk2）水平升高，这意味着cx32缺陷小鼠肿瘤发生过程中MAPK相互作用途径的激活升高。有趣的是，与野生型肺肿瘤相比，cx32缺失小鼠的肺肿瘤也显示p27Kip1水平降低（P = 0.05）。本研究表明，Cx32/GJIC的缺失在辐射诱导的肝脏肿瘤发生中起着重要作用，重要的是，Cx32也可能在其他组织类型（如肺和肾上腺）的肿瘤抑制和/或肿瘤进展中发挥作用。此外，该小鼠模型表明，MAPK相关通路可能被优先激活，或者相反，在缺乏cx32介导的GJIC的情况下，具有活化MAPK通路的肿瘤可能选择性地进展到更晚期的肿瘤状态。
Loss of connexin expression/gap junction intercellular communication (GJIC) has been correlated with decreased growth control and increased tumorigenesis. Studies utilizing Connexin32 (Cx32)-deficient knockout mice have demonstrated that loss of Cx32 increases susceptibility to chemically induced liver tumorigenesis. Here, in addition to dramatically increased liver tumorigenesis, we show that tumor induction utilizing X-ray radiation resulted in a statistically significant increase in overall tumor burden in Cx32-deficient mice compared with wild-type mice due to tumorigenesis in several other tissues (lung, adrenal, lymph and small intestine) even when excluding prevalent liver tumors. Irradiated Cx32-deficient mice were particularly sensitive to liver tumorigenesis (46% incidence compared with 18% in wild-type mice, P = 0.007) demonstrating that Cx32 functions as a hepatic tumor suppressor in response to radiation-associated mutation events. Cx32-deficient mice also exhibited increased lung tumorigenesis (bronchioloalveolar) with an increased progression to carcinoma when compared with wild-type mice. Two Cx32-deficient mice developed an uncommon, invasive medullary adrenal tumor type (pheochromocytoma) not observed in irradiated wild-type mice. Immunohistochemical analysis revealed increased levels of activated mitogen-activated protein kinase (MAPK) (p44/Erk1, p42/Erk2) in Cx32-deficient mouse liver tumors (P = 0.006), lung tumors (P = 0.056) and adrenal tumors (primary and metastases) compared with wild-type counterparts implicating elevated activation of MAPK-interacting pathways in Cx32-deficient tumorigenesis. Interestingly, lung tumors from Cx32-deficient mice also demonstrated decreased p27Kip1 levels compared with wild-type lung tumors (P = 0.05). This study demonstrates that loss of Cx32/GJIC plays a significant role in radiation-induced tumorigenesis of the liver and importantly that Cx32 may also play a role in tumor suppression and/or tumor progression in other tissue types such as lung and adrenal gland. Additionally, this mouse model suggests that MAPK-related pathways may be preferentially activated or conversely that tumors harboring activated MAPK pathways may selectively progress towards more advanced tumor states in the absence of Cx32-mediated GJIC.