Reduced phosphorylated ATM expression is associated with poor prognosis and gemcitabine resistance in pancreatic cancer. Reduced phosphorylated ATM expression is associated with poor prognosis and gemcitabine resistance in pancreatic cancer

Background & Aims: Loss of ataxia-telangiectasia mutated, occurring in patients with multiple primary malignancies, including pancreatic cancer, is associated with poor prognosis. This study investigated the detailed molecular mechanism through which ataxia-telangiectasia mutated expression affects the prognosis of pancreatic-cancer patients Methods: Ataxia-telangiectasia mutated and phosphorylated ataxia-telangiectasia mutated levels in pancreatic-cancer patients who underwent surgical resection were analyzed using immunohistochemistry staining. RNA sequencing was performed on ataxia-telangiectasia mutated-knockdown pancreatic-cancer cells to elucidate the mechanism underlying the involvement of ataxia-telangiectasia mutated in pancreatic cancer. Results: Immunohistochemical analysis showed that 15.3% and 27.8% of clinical samples had low levels of ataxia-telangiectasia mutated and phosphorylated ataxia-telangiectasia mutated, respectively. Low phosphorylated ataxia-telangiectasia mutated expression substantially reduced overall and disease-free survival in pancreatic-cancer patients. Loss of ataxia-telangiectasia mutated promoted MET and NTN1 over-expression via hypoxia-inducible factor-1α, thereby enhancing pancreatic-cancer cell proliferation and migration. Conclusions: These results demonstrate that the loss of ataxia-telangiectasia mutated activates downstream proto-oncogenes, inhibits apoptosis, and promotes tumor growth; moreover, loss of phosphorylated ataxia-telangiectasia mutated leads to poor prognosis in pancreatic-cancer patients. Thus, ataxia-telangiectasia mutated may serve as a potential molecular marker to monitor patient prognosis and as a potential target for pancreatic cancer therapy Overall design: RNA expression profile of ATM-knockdown MIA-PaCa2 and SUIT-2 cells. Total RNA was extracted from the ATM-knockdown MIA-PaCa2 and SUIT-2 cells.

研究背景与目的：共济失调毛细血管扩张症突变蛋白（ataxia-telangiectasia mutated, ATM）缺失常见于包括胰腺癌在内的多原发恶性肿瘤患者，与不良预后相关。本研究旨在探究ATM表达影响胰腺癌患者预后的具体分子机制。
研究方法：采用免疫组化染色分析接受手术切除的胰腺癌患者的ATM及磷酸化ATM（phosphorylated ataxia-telangiectasia mutated, p-ATM）表达水平；对ATM敲低的胰腺癌细胞进行RNA测序，以阐明ATM参与胰腺癌发生发展的潜在分子机制。
研究结果：免疫组化分析显示，分别有15.3%和27.8%的临床样本存在低水平ATM和低水平p-ATM表达。低水平p-ATM表达显著降低胰腺癌患者的总生存期与无病生存期。ATM缺失通过缺氧诱导因子-1α（hypoxia-inducible factor-1α, HIF-1α）促进MET与NTN1的过表达，进而增强胰腺癌细胞的增殖与迁移能力。
研究结论：上述结果表明，ATM缺失可激活下游原癌基因、抑制细胞凋亡并促进肿瘤生长；此外，p-ATM缺失会导致胰腺癌患者预后不良。因此，ATM可作为监测患者预后的潜在分子标志物，同时也可作为胰腺癌治疗的潜在靶点。
整体实验设计：本数据集包含ATM敲低的MIA-PaCa2与SUIT-2细胞的RNA表达谱。实验提取了上述ATM敲低的MIA-PaCa2及SUIT-2细胞的总RNA。