Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation

Abstract

Genome-wide association studies have identified several loci associated with pancreatic cancer risk; however, the mechanisms by which genetic factors influence the development of sporadic pancreatic cancer remain largely unknown. Here, by using genome-wide association analysis and functional characterization, we identify a long intergenic noncoding RNA (lincRNA), LINC00673, as a potential tumor suppressor whose germline variation is associated with pancreatic cancer risk. LINC00673 is able to reinforce the interaction of PTPN11 with PRPF19, an E3 ubiquitin ligase, and promote PTPN11 degradation through ubiquitination, which causes diminished SRC-ERK oncogenic signaling and enhanced activation of the STAT1-dependent antitumor response. A G>A change at rs11655237 in exon 4 of LINC00673 creates a target site for miR-1231 binding, which diminishes the effect of LINC00673 in an allele-specific manner and thus confers susceptibility to tumorigenesis. These findings shed new light on the important role of LINC00673 in maintaining cell homeostasis and how its germline variation might confer susceptibility to pancreatic cancer.

Inherited pancreatic cancer

“…This association subsequently replicated in a Han Chinese population (rs11655237, OR = 1.26, P = 3.95×10 −14 ) 161 . Through its epigenetic regulation of gene expression, LINC00673 may function as an oncogene in several types of cancers.…”

“…In contrast, expression of LINC00673 was significantly lower in PDAC cancer cells than in normal cells and tissues and overexpression of LINC00673 in the PDAC cell line substantially reduced the rate of cell proliferation. It was found that the single-nucleotide change at rs11655237 creates a miR-1231 binding site, which diminishes the effect of LINC00673 in an allele-specific manner and thus confer susceptibility to pancreatic tumorigenesis 161 .…”

Long intergenic noncoding RNA 00673 promotes non-small-cell lung cancer metastasis by binding with EZH2 and causing epigenetic silencing of HOXA5

“…However, a recent study on pancreatic cancer revealed significantly lower expression of linc00673 in cancerous cells and tissues. Further, linc00673 reportedly acted as a tumor suppressor through regulation of the protein tyrosine phosphatase PTPN1 [21]. LncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) was previously reported to be upregulated in melanoma cells., whereafter, Sun et al found that SPRY4-IT1 expression was downregulated and correlated with a poor prognosis of NSCLC [22].…”

Genomic Insight into the Role of lncRNAs in Cancer Susceptibility

“…They found that the rs1899663 T allele was associated with BPH risk and the rs12826786 T allele was associated with both BPH and prostate cancer susceptibility. Even though the mechanisms underlying these two SNPs and HOTAIR are still unclear, we might find some clues from other non-coding RNAs such as the pancreatic cancer-associated long intergenic noncoding RNA lincRNA LINC00673 [61]. As shown in Figure 1A, LINC00673 is a tumor suppressor and can increase the interaction between PTPN11 and an E3 ubiquitin ligase PRPF19.…”