肺癌是全球范围内最严重的恶性肿瘤之一，无论是发病率还是死亡率，都远高于其他的肿瘤类型。在组织病理临床上肺癌分为非小细胞肺癌和小细胞肺癌。非小细胞肺癌包括肺腺癌、肺鳞癌、神经内分泌癌、腺鳞癌等，其中，肺腺癌占40%-55%。根据肿瘤存在的位置，肺腺癌可分为非终末呼吸单元肺腺癌和终末呼吸单元肺腺癌。非终末呼吸单元肺腺癌是一类独特的肺腺癌，具有复杂的腺样结构和黏液特征，分子水平的研究数据也显示了独特的基因组表达谱和miRNA表达谱。值得关注的是，非终末呼吸单元肺腺癌患者预后较差，患者极少携带EGFR、EML4-ALK等基因突变，所以无法进行酪氨酸激酶抑制剂TKI药物靶向治疗。目前，我国和日本的学者研究数据报告建议在临床病理诊断和治疗中，将非终末呼吸单元肺腺癌作为一类独立的肺腺癌类型。然而，这一类腺癌的诊断和治疗分子标志物尚有待发掘。因此，本研究以非终末呼吸单元肺腺癌为研究对象，收集该类患者的临床病例信息，总结了其遗传和病理学特征。本研究汇总分析了肺早期发育机制和肺腺癌异常发育的相关文献，支持Wnt/β-catenin信号通路促进肺腺癌的发生和发展。此外，Sox2与肿瘤的恶性表型相关。基于此，本研究通过qPCR和RT-PCR方法筛选了系列Wnt/β-catenin信号通路成员和相关的干细胞标志物的表达水平，从中确定了出两个关键蛋白β-catenin和SOX2。本论文也利用免疫组化的实验方法对临床患者样本进行原位组织表达分析。本论文研究得到如下结果：

临床病例对比分析表明，与终末呼吸单元肺腺癌相比，在相同原发肿瘤体积情况下，非终末呼吸单元肺腺癌累及淋巴结范围更广(P ＜ 0.05)，发生累及叶段支气管(P ＜ 0.05)、神经侵犯和脉管瘤栓的概率更高。这提示了相比于终末呼吸单元肺腺癌，非终末呼吸单元肺腺癌具有较高侵袭性。

转录水平表达分析发现，与同患者癌旁组织相比，Sox2在肺腺癌组织中表达上升 (P = 0.11)。结合先前研究中对Wnt/β-catenin信号通路调控肺腺癌肿瘤细胞干性的报道，提示了通路关键分子β-catenin在肺腺癌干性调控中起关键作用。

原位组织表达分析发现，β-catenin在非终末呼吸单元肺腺癌和终末呼吸单元肺腺癌的肺实质、腺体样结构、气道结构均表达。在两种肺腺癌类型中，β-catenin的细胞质表达水平无显著差异(P = 0.9033)。但相较于终末呼吸单元肺腺癌，非终末呼吸单元肺腺癌中呈β-catenin核阳性的细胞比例显著升高(P ＜ 0.05)，提示了Wnt/β-catenin信号通路在该分型中具有更高的活化水平。

在肺腺癌肿瘤原位分析中，SOX2仅局限于气道上皮与腺体细胞中表达。且非终末呼吸单元肺腺癌样本中呈SOX2细胞核阳性的细胞比例显著高于终末呼吸单元肺腺癌（P ＜ 0.005）。这提示了非终末呼吸单元肺腺癌的细胞学来源，并表明了SOX2具有作为区分两种肺腺癌的分子标志物的潜力。

综上，Wnt/β-catenin信号通路同时作用于非终末呼吸单元肺腺癌和终末呼吸单元肺腺癌，且在前者中显著激活，这提示了该通路与肺腺癌恶性程度的关联性，也提示了Wnt/β-catenin通路作为肺腺癌潜在治疗靶点的可能性。同时，SOX2被证明是气道附近的非终末呼吸单元肺腺癌的潜在标志物，可用于辅助病理诊断，为此类腺癌的临床诊疗提供参考。

SOX2与β-catenin信号通路相互作用及其在非终末呼吸单元肺腺癌发生、发展和预后中的作用有待进一步的研究。

Lung cancer is one of the most serious malignant tumors in the world. Both the incidence rate and mortality are far higher than other tumor types. Based on the histopathological clinical practice, lung cancer is divided into non-small cell lung cancer and small cell lung cancer. Non small cell lung cancer includes lung adenocarcinoma, lung squamous cell carcinoma, neuroendocrine carcinoma, adenosquamous carcinoma, among which lung adenocarcinoma accounts for 40% - 55%. Based on the location of the tumor, lung adenocarcinoma can be divided into non distal respiratory unit lung adenocarcinoma and distal respiratory unit lung adenocarcinoma. Non distal respiratory unit lung adenocarcinoma is a unique type of lung adenocarcinoma with complex adenoid structure and mucinous characteristics. Molecular level research data also shows unique genomic and miRNA expression profiles. Notably, patients with non distal respiratory unit lung adenocarcinoma have a poor prognosis, and they rarely carry gene mutations such as EGFR and EML4-ALK. So it impossible to perform targeted treatment with tyrosine kinase inhibitor TKI drugs. At present, scholars in China and Japan suggest that non distal respiratory unit lung adenocarcinoma should be considered as an independent type of lung adenocarcinoma in clinical pathological diagnosis and treatment. However, molecular markers for the diagnosis and treatment of this type of adenocarcinoma still need to be explored. Therefore, this study focuses on non distal respiratory unit lung adenocarcinoma as the research object, collects clinical case information of such patients, and summarizes their genetic and pathological characteristics. We have summarized and analyzed relevant literature on the mechanisms of early lung development and abnormal development of lung adenocarcinoma, supporting Wnt/β-catenin signaling pathway promotes the occurrence and development of lung adenocarcinoma. In addition, Sox2 is associated with the malignant phenotype of tumors. Based on this, a series of Wnt/β-catenin pathway members have been screened with qPCR and RT-PCR methods and related stem cell markers have been identified, from which β-catenin and SOX2 have been identified. This paper also utilizes immunohistochemical experimental methods to perform in situ tissue expression analysis on clinical patient samples. The results of this paper are as follows:

1. Comparative analysis of clinical cases shows that compared with distal respiratory unit lung adenocarcinoma, non distal respiratory unit lung adenocarcinoma has a wider range of lymph nodes (P < 0.05) and a higher probability of involving lobar bronchi (P < 0.05), nerve invasion, and vascular tumor thrombi under the same primary tumor volume. This suggests that compared to distal respiratory unit lung adenocarcinoma, non distal respiratory unit lung adenocarcinoma is more invasive.

2. Transcription level expression analysis found that compared to the adjacent tissues of the same patient, the expression of Sox2 increased in lung adenocarcinoma tissues (P = 0.11). And the expression level of CD133, a cell stem marker, increased in tumor tissue. Combined with previous studies on stemness of  the Wnt/β-catenin signaling pathway in lung adenocarcinoma, β-catenin may play a crucial role in stemness regulation of lung adenocarcinoma.

3. In situ tissue expression analysis revealed that, β-catenin is expressed in the lung parenchyma, glandular like structure, and airway structure of in both non distal respiratory unit lung adenocarcinoma and distal respiratory unit lung adenocarcinoma. Among the two types of lung adenocarcinoma, there was no significant difference in cytoplasmic expression level of β-catenin (P = 0.9033). But compared to distal respiratory unit lung adenocarcinoma, non distal respiratory unit lung adenocarcinoma shows increased proportion of cells with positive β-catenin nuclei(P < 0.05), indicating Wnt/ β-catenin signaling pathway has a higher level in this subtype.

4. In situ tissue expression analysis revealed that, SOX2 was only expressed in airway epithelium and gland cells. The proportion of cells with SOX2 nuclear positivity in non distal respiratory unit lung adenocarcinoma samples was significantly higher than that in distal respiratory unit lung adenocarcinoma samples (P < 0.005). This suggests the cytological origin of non distal respiratory unit lung adenocarcinoma and suggests the potential of SOX2 as a molecular marker for distinguishing between two types of lung adenocarcinoma.

In summary, Wnt/β-catenin signaling pathway acts simultaneously on non distal respiratory unit lung adenocarcinoma and distal respiratory unit lung adenocarcinoma, and is significantly activated in the former type. This indicates a correlation between Wnt/ β-catenin pathway and malignancy of lung adenocarcinoma. And Wnt/ β-catenin pathway may be a potential therapeutic target for lung adenocarcinoma. Meanwhile, SOX2 has been proven to be a potential biomarker for non distal respiratory unit lung adenocarcinoma near the airway, which contributes to auxiliary pathological diagnosis, provides a reference for clinical diagnosis and treatment of such type of adenocarcinoma.

Furthermore, previous studies have shown that Wnt in lung adenocarcinoma stem cell like tumor cells/ β-catenin pathway is highly activated, and tumor stem cell marker SOX2 can promote tumor cell proliferation, epithelial mesenchymal transformation and cell migration, and molecular interaction prediction also suggests that there is a potential relationship between the two. SOX2 and β-catenin signaling pathway and its role in the occurrence, development, and prognosis of non distal respiratory unit lung adenocarcinoma will be key for further research.

In the future, we needs to focus on the interaction of SOX2 and β-catenin signaling pathway and its role in the occurrence, development, and prognosis of non distal respiratory unit lung adenocarcinoma.