C8orf76 Promotes Gastric Tumorigenicity and Metastasis by Directly Inducing lncRNA DUSP5P1 and Associates with Patient Outcomes

Abstract

Purpose: We identified for the first time that C8orf76 (chromosome 8 open reading frame 76) is preferentially amplified in gastric cancer. We elucidated its role and clinical significance in gastric carcinogenesis. Experimental Design: The clinical impact of C8orf76 was assessed in 592 patients with gastric cancer. The biological function of C8orf76 was studied in vitro, in vivo, and in gastric cancer patient-derived organoid models. C8orf76 downstream effector and pathways were identified by RNA sequencing, chromatin immunoprecipitation sequencing, luciferase reporter, and electrophoretic mobility shift assay. Results: C8orf76 was upregulated in 69.74% and 65.71% of two independent cohorts of gastric cancers and was positively associated with C8orf76 amplification. Multivariate analysis showed that gastric cancer patients with C8orf76 amplification (cohort I, n ¼ 129; cohort II, n ¼ 107) or overexpression (n ¼ 356) had a significantly shortened survival. C8orf76 significantly promoted gastric cancer cell proliferation, cell-cycle transformation, and migration/invasion, but suppressed cell apoptosis. Silencing C8orf76 expression exerted opposite effects in vitro and significantly inhibited xenograft tumor growth, lung metastasis, and liver metastasis in nude mice. Silencing C8orf76 also significantly suppressed the growth of patient-derived organoids. Mechanically, C8orf76 activated MAPK/ERK signaling cascade. C8orf76 directly bound to the promoter region of lncRNA dual specificity phosphatase 5 pseudogene 1 (DUSP5P1) with a binding motif of AGGCTG and activated DUSP5P1 transcription. DUSP5P1 induced MAPK/ERK signaling and promoted gastric tumorigenesis. Knockdown DUSP5P1 abrogated the effect of C8orf76 in activating MAPK/ERK cascade and the tumor-promoting function. Conclusions: C8orf76 directly binds to oncogenic lncRNA DUSP5P1 to induce its expression and activates MAPK signaling. C8orf76 plays a pivotal oncogenic role in gastric carcinogenesis and is an independent prognostic factor for gastric cancer patients.

Long noncoding RNA MIR99AHG promotes gastric cancer progression by inducing EMT and inhibiting apoptosis via miR577/FOXP1 axis

“…Gastric cancer is the fifth most common malignancy with a third highest cancer associated death rate [12]. Recently, various studies have suggested that lncRNAs are closely related to the carcinogenesis and development of GC [13][14][15][16][17]. LncRNA TINCR could promote the metastatic ability of GC cells by regulating the stability of KLF2 [18,19].…”

FOXC1-induced LINC01123 acts as a mediator in triple negative breast cancer

“…Prior studies validated that LINC00460 is a PRDX1-initiated lncRNA in head and neck squamous cell carcinoma [20]. C8orf76 directly binds to lncRNA DUSP5P1 promoter and induces lncRNA expression in gastric cancer [21]. However, the transcription of LINC01123 in TNBC remains obscure.…”

The Novel Role of LINC01235 in Metastasis of Gastric Cancer Cells by Inducing Epithelial-mesenchymal Transition

“…Research has shown that the veyear survival rate of patients with advanced GC is < 20% 20,21 . Increasing numbers of studies have found that lncRNAs can act as critical regulators in GC metastasis and tumor growth, potentially becoming promising targets for GC treatment [22][23][24] . LINC01235 is a large intergenic noncoding RNA that is located on human chromosome 9p23 and has three exons.…”