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Long noncoding RNAs (lncRNA) are dysregulated in various human cancers and control tumor development and progression. However, the upstream mechanisms underlying their dysregulation remain unclear. Here, we demonstrate that the expression of hepatocyte nuclear factor 1 homeobox A antisense RNA 1 (HNF1A-AS1) is significantly upregulated in gastric cancer tissues. Overexpression of HNF1A-AS1 enhanced cell proliferation and promoted cell-cycle progression, whereas knockdown of HNF1A-AS1 elicited the opposite effects. Early growth response protein 1 (EGR1) directly bound the HNF1A-AS1 promoter region and activated its transcription. Overexpression of EGR1 enhanced cell proliferation and promoted cell-cycle promotion, similar to the function of HNF1A-AS1. HNF1A-AS1 functioned as competing endogenous RNA (ceRNA) by binding to miR-661, upregulating the expression of cell division cycle 34 (CDC34), which is a direct target of miR-661. EGR1 and HNF1A-AS1 enhanced the expression of cyclin-dependent kinase 2 (CDK2), CDK4, and cyclin E1 but inhibited the expression of p21 by promoting CDC34-mediated ubiquitination and degradation of p21. Taken together, these findings suggest that EGR1-activated HNF1A-AS1 regulates various pro- and antigrowth factors to promote the development of gastric cancer, implicating it as a possible target for therapeutic intervention in this disease.Significance: This study provides novel insights into mechanisms by which the noncoding RNA HNF1A-AS1 contributes to gastric cancer progression through modulation of the cell cycle. Cancer Res; 78(20); 5877–90. ©2018 AACR.

Figure S1 showed that the overexpression and knockdown efficiency of HNF1A-AS1 in both GC cells and the proliferation of GC cells transfected with SI-HNF1A-AS1-2 were inhibited. Figure S2 indicated that the migration, invasion and cell cycle progression of GC cells transfected with SI-HNF1A-AS1-2 were inhibited. Table S1 showed sequences of primers.

Long noncoding RNAs (lncRNA) are dysregulated in various human cancers and control tumor development and progression. However, the upstream mechanisms underlying their dysregulation remain unclear. Here, we demonstrate that the expression of hepatocyte nuclear factor 1 homeobox A antisense RNA 1 (HNF1A-AS1) is significantly upregulated in gastric cancer tissues. Overexpression of HNF1A-AS1 enhanced cell proliferation and promoted cell-cycle progression, whereas knockdown of HNF1A-AS1 elicited the opposite effects. Early growth response protein 1 (EGR1) directly bound the HNF1A-AS1 promoter region and activated its transcription. Overexpression of EGR1 enhanced cell proliferation and promoted cell-cycle promotion, similar to the function of HNF1A-AS1. HNF1A-AS1 functioned as competing endogenous RNA (ceRNA) by binding to miR-661, upregulating the expression of cell division cycle 34 (CDC34), which is a direct target of miR-661. EGR1 and HNF1A-AS1 enhanced the expression of cyclin-dependent kinase 2 (CDK2), CDK4, and cyclin E1 but inhibited the expression of p21 by promoting CDC34-mediated ubiquitination and degradation of p21. Taken together, these findings suggest that EGR1-activated HNF1A-AS1 regulates various pro- and antigrowth factors to promote the development of gastric cancer, implicating it as a possible target for therapeutic intervention in this disease. Significance: This study provides novel insights into mechanisms by which the noncoding RNA HNF1A-AS1 contributes to gastric cancer progression through modulation of the cell cycle. Cancer Res; 78(20); 5877–90. ©2018 AACR.