Chida Kohei, Oshi Masanori, Roy Arya Mariam, Sato Takumi, Endo Itaru, Takabe Kazuaki
Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, NY 14263, USA.
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine Yokohama, Kanagawa 236-0004, Japan.
Am J Cancer Res. 2023 Aug 15;13(8):3638-3649. eCollection 2023.
Alcohol dehydrogenase (ADH) oxidizes alcohol into acetaldehyde (AA), which is a known carcinogen. Aldehyde dehydrogenase (ALDH) oxidizes AA into acetate. Therefore, pancreatic cancer that expresses a high level of ADH1B that generates more AA is expected to be associated with aggressive cancer. On the other hand, given that the differentiated cells that retain their cellular functions typically exhibit lower proliferation rates, it remains unclear whether pancreatic adenocarcinoma (PDAC) with high gene expression is linked to aggressive features in patients. The Cancer Genome Atlas ( = 145) was used to obtain data of PDAC patients and GSE62452 cohort ( = 69) was used as a validation cohort. PDAC with high expression was associated with less cancer cell proliferation as evidenced by lower expression and lower histological grade; with a higher fraction of stromal cells consistent with less proliferative cancer. PDAC with high expression also had lower homologous recombination deficiency and mutation rates, lower and mutation rates. expression correlated with expression in PDAC, but not with DNA repair genes. High expression PDAC was associated with high infiltration of anti-cancerous CD8 T cells and pro-cancerous M2 macrophages but with lower levels of Th1 T cells, with a higher cytolytic activity. PDAC patients with a high expression had better disease-specific survival (DSS) and overall survival (OS) and was an independent prognostic biomarker for both DSS (HR = 0.89, 95% CI = 0.80-0.99, = 0.045) and OS (HR = 0.90, 95% CI = 0.82-0.99, = 0.044) in multivariate analysis. In conclusion, PDAC with high expression had less cell proliferation and malignant features, along with higher immune cell infiltration, and had a better prognosis.
酒精脱氢酶（ADH）将酒精氧化为乙醛（AA），乙醛是一种已知的致癌物。醛脱氢酶（ALDH）将乙醛氧化为乙酸盐。因此，表达高水平ADH1B从而产生更多乙醛的胰腺癌预计与侵袭性癌症相关。另一方面，鉴于保留细胞功能的分化细胞通常增殖率较低，尚不清楚高基因表达的胰腺腺癌（PDAC）是否与患者的侵袭性特征有关。使用癌症基因组图谱（n = 145）获取PDAC患者的数据，并将GSE62452队列（n = 69）用作验证队列。高表达的PDAC与较少的癌细胞增殖相关，低表达和较低的组织学分级证明了这一点；基质细胞比例较高，这与增殖性较低的癌症一致。高表达的PDAC还具有较低的同源重组缺陷和突变率、较低的KRAS和BRAF突变率。ALDH1A1表达与PDAC中的ALDH1B1表达相关，但与DNA修复基因无关。高ALDH1A1表达的PDAC与抗癌CD8 T细胞和促癌M2巨噬细胞的高浸润相关，但Th1 T细胞水平较低，具有较高的细胞溶解活性。高ALDH1A1表达的PDAC患者具有更好的疾病特异性生存（DSS）和总生存（OS），并且在多变量分析中，ALDH1A1是DSS（HR = 0.89，95% CI = 0.80 - 0.99，P = 0.045）和OS（HR = 0.90，95% CI = 0.82 - 0.99，P = 0.044）的独立预后生物标志物。总之，高ALDH1A1表达的PDAC细胞增殖和恶性特征较少，免疫细胞浸润较高，预后较好。
