C8orf76 promotes gastric tumorigenicity and metastasis by directly inducing lncRNA DUSP5P1 and associates with patient outcomes

Purpose: We identified for the first time that C8orf76 (chromosome 8 open reading frame 76) is preferentially amplified in gastric cancer (GC). We elucidated its role and clinical significance in gastric carcinogenesis. Experimental Design:The clinical impact of C8orf76 was assessed in 592 GCs. The biological function of C8orf76 was studied in vitro, in vivo and in GC patient-derived organoid models. C8orf76 downstream effector and pathways were identified by RNA-sequencing, ChIP-sequencing, luciferase reporter and electrophoretic mobility shift assay. Results:C8orf76 was upregulated in 69.74% and 65.71% of two independent cohorts of GCs and was positively associated with C8orf76 amplification. Multivariate analysis showed that GC patients with C8orf76 amplification (cohort I n=129; cohort II, n=107) or overexpression (n=356) had a significantly shortened survival. C8orf76 significantly promoted GC cell proliferation, cell cycle transformation, 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 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 pivotal oncogenic role in gastric carcinogenesis and is an independent prognostic factor for GC patients.

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