The PDAC risk variant of LINC00673 is targeted by miR-1231 to promote PDAC growth.
Major finding: The PDAC risk variant of LINC00673 is targeted by miR-1231 to promote PDAC growth.
Mechanism: LINC00673 induces PTPN11 degradation to inhibit SRC–ERK signaling and activate STAT1.
Impact: Perturbation of interactions between lincRNAs and miRNAs may drive tumorigenesis.
Genome-wide association studies (GWAS) have identified genetic loci which exhibit associations with cancer and are frequently located in regions encoding long intergenic noncoding RNAs (lincRNA). Zheng, Huang, and colleagues reanalyzed their pancreatic ductal adenocarcinoma (PDAC) GWAS dataset of a Han Chinese population and identified the lincRNA LINC00673 as a new PDAC susceptibility locus. Evaluation of the SNPs located in LINC00673 revealed that rs11655237 was associated with susceptibility to PDAC and is located within a presumptive binding site for miR-1231. Binding of miR-1231 to LINC00673 was decreased in the presence of the rs11655237[A] allele compared to the rs11655237[G] allele. LINC00673 expression was lower in PDAC tumors and cell lines compared to normal tissues and cells, and analysis of normal pancreas tissues adjacent to PDAC tumors revealed that patients with the rs11655237 GG genotype exhibited greater LINC00673 levels than patients with the GA or AA genotypes. Overexpression of the rs11655237[G] allele in PDAC cell lines resulted in reduced proliferation, a reduction in anchorage-independent colony formation, and decreased xenograft growth. The rs11655237[G] allele promoted the pre-mRNA processing factor 19 (PRPF19)–mediated ubiquitination and subsequent degradation of protein tyrosine phosphatase, non-receptor type 11 (PTPN11), a signaling molecule that regulates cellular processes such as cellular growth, mitotic cycle, and oncogenic transformation. Loss of PTPN11 signaling resulted in the inhibition of the protumorigenic SRC–ERK signaling axis and induced a STAT1-mediated antitumor response. Consistent with these findings, overexpression of the rs11655237[A] allele in PDAC cell lines resulted in increased cell growth and decreased PTPN11 ubiquitination. Together, these results identify the lincRNA LINC00673 as a potential tumor suppressor in PDAC and describe a mechanism by which the cooperation between a lincRNA risk variant and an miRNA promotes tumorigenesis.