Integrative network analysis identified master regulatory long non-coding RNAs underlying the squamous subtype of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with limited treatment options currently. Due to the small volume of the pancreas located in a special anatomic position and an extremely high stromal infiltration, PDAC can be hardly diagnosed in the early stage, leading to a low survival rate. Similar to many other malignancies, PDAC was reported to have three to five distinct subtypes based on transcriptomic classifications. One recent study identified four molecularly distinct subtypes associated with different clinical characteristics in PDAC: squamous, pancreatic progenitor, immunogenic, and aberrantly differentiated endocrine exocrine (ADEX). Among them, the squamous subtype is associated with the worst prognosis, yet the underlying regulatory mechanism remains elusive. Long non-coding RNAs (lncRNAs) are known to play important roles in gene regulation, and dysregulations of lncRNAs have been reported in many human diseases including cancers. Here, we inferred a lncRNA regulatory network by integrative network analysis and prioritized key lncRNAs as potential master regulators of the squamous subtype including TGFB2-AS1, AL138930.1, LINC01705, AC245041.1, UCA1, and NKILA. Some of these lncRNAs, such as UCA1, have been demonstrated to be dysregulated in multiple cancer types including pancreatic cancer. We further demonstrated that the upregulation of UCA1 and NKILA in the squamous subtype were likely due to the promoter hypomethylation. Moreover, we found the positive regulatory relationships between two antisense lncRNAs, TGFB2-AS1 and NKILA, with their sense genes, TGFB2 and PMEPA1, respectively. Survival analysis based on multiple independent datasets confirmed the clinical associations of these lncRNAs. In summary, our study gained novel insights into the lncRNA regulatory mechanisms and provided potential therapeutic targets specifically for the squamous subtype of PDAC.