BACKGROUND

Many studies have reported the roles of the extracellular hypoxia microenvironment in the tumorigenesis and metastasis of multiple cancers. However, long noncoding RNAs (s) that induce cancer oncogenicity and metastasis of pancreatic cancer (PC) under hypoxia conditions remain unclear.

METHODS

In PC cells, the expression levels of s in different conditions (normoxia or hypoxia) were compared through RNA sequencing (RNA-seq). The effects of the zinc finger E-box-binding homeobox 1 () antisense on PC cells cultured in normoxia/hypoxia medium were measured through gain and loss-of-function experiments. Fluorescence hybridization and luciferase reporter assays in addition to studies were utilized to explore the adaptive mechanisms of in the hypoxia-promoted proliferation, migration, and invasion ability of PC cells. Moreover, the level of and its associated targets or pathways were investigated in both PC and pancreatic normal tissues.

RESULTS

RNA-seq revealed that was significantly upregulated in PC cells under hypoxia conditions. The expression level was closely associated with poor prognosis of PC patients. Knockdown of suppressed the proliferation, migration, and invasion of PC cells as well as PC xenograft tumor growth . In PC cells, RNAi-mediated reduction of inhibited zinc finger E-box-binding homeobox 1 (), while overexpression rescued expression, indicating that promotes expression. Moreover, hypoxia-inducible factor-1α (α)induced the expression of by binding to the promoter, which contains a putative hypoxia response element (HRE). Mechanistically, scaffolded the interaction among α, , and histone deacetylase 1 (), leading to deacetylation-mediated stabilization of α. We further revealed that induced the deacetylase capacity of to suppress the acetylation or degradation of α, improving α assembly. Thus, hypoxia-induced facilitated transcription and the stability of α, which promoted the metastasis of PC cells. Clinically, dysregulated and α expression was significantly correlated with histological grade, lymphatic metastasis, and distant metastasis in PC patients.

CONCLUSIONS

Our results emphasized that the positive reciprocal loop of α/// contributes to hypoxia-promoted oncogenicity and PC metastasis, indicating that it might be a novel therapeutic target for PC.