Overexpression of muscarinic receptor 3 promotes metastasis and predicts poor prognosis in non-small-cell lung cancer.
Overexpression of muscarinic receptor 3 promotes metastasis and predicts poor prognosis in non-small-cell lung cancer.
复制标题
DOI：
10.1097/jto.0000000000000066
复制
发表时间：
2014-02
期刊：
影响因子：
--
通讯作者：
Xie C
中科院分区：
文献类型：
--
作者：
Lin G;Sun L;Wang R;Guo Y;Xie C
慢性阻塞性肺疾病(COPD)是肺癌发生的独立危险因素，但其发病机制尚不完全清楚。M受体3(M3R)参与了小细胞肺癌的发生发展和COPD的病理过程。我们推测M3R可能与肺癌的发生有关，尤其是在COPD患者中。应用免疫组织化学方法检测148例非小细胞肺癌(NSCLC)石蜡包埋标本中M3R的表达与临床特征的关系。采用M3R激动剂和siRNA处理，研究M3R在NSCLC细胞中的作用。免疫印迹和酶谱检测M3R对PI3K/Akt/基质金属蛋白酶9信号通路的影响。M3R在NSCLC中的表达显著升高，并与NSCLC患者的肿瘤转移和生存不良有关。非小细胞肺癌合并慢性阻塞性肺病患者M3R的表达明显高于无慢性阻塞性肺病患者(P=0.0014)。M3R的表达与1s用力呼气量百分比(r=0.7017，p<；0.0001)、1s用力呼气量/用力肺活量(r=0.5057，p<；0.0001)呈负相关，与吸烟史呈正相关。M3R表达下调导致NSCLC细胞株A549和L78的迁移和侵袭能力受到抑制。此外，M3R通过PI3K/Akt途径增强基质金属蛋白酶9的表达和活性，从而促进NSCLC细胞的迁移和侵袭。我们的结果提示，M3R在NSCLC中的过度表达促进了NSCLC的进展，这可能有助于COPD患者肺癌的发生。M3R可能是治疗肺癌，特别是COPD患者的另一个药理靶点。
Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer development, but the mechanism is not fully understood. Muscarinic receptor 3 (M3R) has been found to be involved in the progression of small-cell lung cancer and the pathological process of COPD. We hypothesized that M3R may contribute to lung cancer development, especially in patients with COPD. The correlation between M3R expression and clinical features of non–small-cell lung cancer (NSCLC) was evaluated in 148 paraffin-embedded archived NSCLC specimens with the use of immunohistochemistry. M3R agonist and siRNA treatments were used to study the role of M3R in NSCLC cell lines. Western blotting and zymography were used to examine the impact of M3R on the PI3K/Akt/matrix metalloproteinase 9 signaling pathway. The expression of M3R in NSCLC was significantly increased and correlated with tumor metastasis and poor survival of NSCLC patients. NSCLC patients with COPD showed higher expression of M3R than those without COPD (p = 0.0014). Moreover, M3R expression was inversely related to percent forced expiratory volume in 1 second (r = 0.7017, p < 0.0001) and forced expiratory volume in 1 second /forced vital capacity (r = 0.5057, p < 0.0001), but positively related to smoking history. Down-regulation of M3R resulted in the inhibition of migration and invasion ability of NSCLC cell lines A549 and L78. Furthermore, M3R enhanced the expression and activity of matrix metalloproteinase 9 through PI3K/Akt, which promoted the migration and invasion of NSCLC cell lines. Our results suggest that overexpression of M3R in NSCLC promotes the progression of NSCLC, which could contribute to lung cancer development in COPD patients. M3R could be another pharmacological target in lung cancer, especially in COPD patients.