Table1_ELK1 Enhances Pancreatic Cancer Progression Via LGMN and Correlates with Poor Prognosis.DOC

Pancreatic cancer is one of the most lethal cancers and its prognosis is extremely poor. Clarification of molecular mechanisms and identification of prognostic biomarkers are urgently needed. Though we previously found that LGMN was involved in pancreatic carcinoma progression, the upstream regulation of LGMN remains unknown. We used reliable software to search for the potential transcription factors that may be related with LGMN transcription, we found that ELK1 could be a new regulator of LGMN transcription that binded directly to the LGMN promoter. Moreover, knocking down of ELK1 reduced pancreatic cancer cells proliferation, invasion and survival, while LGMN restored the malignancy of pancreatic cancer in vitro and in vivo. Overexpression of ELK1 further increased cancer cells proliferation, invasion and survival. Clinically, ELK1 and LGMN were positively correlated with clinical stage, degree of differentiation and Lymph node infiltration. ELK1 and LGMN were identified as independent prognostic factors for overall survival. The patients with low expression of ELK1/LGMN survived an average of 29.65 months, whereas those with high expression of ELK1/LGMN survived an average of 16.67 months. In conclusive, our results revealed a new mechanism by which ELK1 promoted the progression of pancreatic cancer via LGMN and conferred poor prognosis.

胰腺癌是致死性最高的恶性肿瘤之一，预后极差。阐明其分子机制并鉴定预后生物标志物迫在眉睫。尽管我们此前已发现LGMN参与胰腺癌的进展过程，但LGMN的上游调控机制仍未明确。我们借助可靠的生物信息学软件筛选与LGMN转录调控相关的潜在转录因子，结果发现ELK1可作为LGMN转录的新型调控因子，能够直接结合LGMN的启动子区域。此外，敲低ELK1可抑制胰腺癌细胞的增殖、侵袭与存活能力；而恢复LGMN的表达则可在体内外逆转胰腺癌细胞的恶性表型。过表达ELK1则可进一步增强胰腺癌细胞的增殖、侵袭与存活能力。临床分析显示，ELK1与LGMN的表达水平与胰腺癌的临床分期、分化程度及淋巴结浸润程度呈正相关。ELK1与LGMN均可作为总生存期的独立预后因子。ELK1/LGMN低表达患者的平均总生存期为29.65个月，而高表达患者的平均总生存期仅为16.67个月。综上，本研究揭示了ELK1通过调控LGMN促进胰腺癌进展并导致不良预后的全新机制。