Abstract
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. 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. 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 = 129; cohort II, n = 107) or overexpression (n = 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. 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.
Highlights
Gastric cancer is the third leading cause of cancer-related mortality globally [1, 2]
Using human genome comparative genomic hybridization microarray to profile copy-number variations in gastric cancer patients [5], we have previously demonstrated that copy-number gain frequently occurred in chromosome regions 8q22, 8q24, and 20q11-q13, and was significantly associated with poor survival of gastric cancer patients
C8orf76 mRNA overexpression was confirmed in gastric cancer patients as compared with the adjacent nontumor tissues from The Cancer Genome Atlas (TCGA) datasets
Summary
Gastric cancer is the third leading cause of cancer-related mortality globally [1, 2]. About half of the gastric cancer exhibits chromosomal instability, including gene copy-number gain and loss [3]. Overexpressed oncogenes by copy-number gain are involved in gastric cancer progression, including HER2, MYC, SRC, EGFR, FGFR1, FGFR2, and colleagues [4,5,6]. The focal amplification of these gene regions and an increased frequency of their amplification are associated with invasive clinico-. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Until now, Trastuzumab is the only approved target agent for a subgroup of gastric cancers with HER2 overexpression [7]. Identification of new factors mediated by gene amplification may provide new insights into the diagnosis and target therapy of gastric cancer
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