吸烟致癌新机制：烟草化合物NNK通过β2AR/SOX4/Akt轴改变腺泡命运诱导胰腺癌发生

吸烟是目前唯一被证实与胰腺癌发生密切相关的环境因素，然而其致癌机制并不明确。“腺泡导管化生(ADM)-上皮内瘤变(PanIN)-胰腺癌(PDAC)”是胰腺癌发生的经典途径。课题组研究发现，NNK可在不同层面调控β2AR/SOX4/Akt轴促进胰腺癌恶性生物学行为。此外，体内实验中，NNK可加重慢性胰腺炎组织纤维化，同时促使ADM发生。体外实验中，NNK可启动腺泡细胞恶性转变，阻断β2AR可抑制NNK的作用。我们推测，NNK可作用于腺泡细胞β2AR/SOX4/Akt轴，改变腺泡细胞“命运”，使其“去分化”和“重编程”，启动胰腺恶性转变；在长期吸烟基础上，NNK可加速“ADM-PanIN-PDAC”进程，导致胰腺癌发生。为证实该假说，我们将采用CoIP、RNA-seq、活细胞工作站等技术，借助胰腺癌转基因小鼠动物模型，探究NNK对胰腺癌发生的影响，揭示其分子机制，丰富吸烟导致胰腺癌发生的理论。

Smoking is the only environmental factor that has been proved to be closely related to pancreatic cancer, but its carcinogenic mechanism is not clear. ‘Acinar ductal metaplasia (ADM)–intraepithelial neoplasia (PanIN)–pancreatic cancer (PDAC)’ is a classic pathway for pancreatic carcinogenesis. Our research group found that NNK could regulate the β2AR / SOX4 / Akt axis at different levels to promote the malignant biological behavior of pancreatic cancer. In addition, in vivo, NNK can aggravate tissue fibrosis in chronic pancreatitis and promote the occurrence of ADM. In vitro, NNK can initiate malignant transformation of acinar cells, β2AR blockage can inhibit the effect of NNK. We speculated that NNK can act on the β2AR/SOX4/Akt axis of acinar cells, determining the 'fate' of acinar cells, promoting its 'dedifferentiation' and 'reprogramming', and initiating malignant transformation of the pancreas. On the basis of long-term smoking, NNK can accelerate the 'ADM-PanIN-PDAC' process, leading to pancreatic cancer. To confirm this hypothesis, we will use CoIP, RNA-seq, living cell workstation and other technologies to explore the effect of NNK on the occurrence of pancreatic cancer by using the transgenic mouse model of pancreatic cancer. In this research, we tend to reveal the underlying mechanism of smoking-induced pancreatic carcinogenesis.