Abstract
Gastric cancer is the fifth most common malignancy but the third leading cause of cancer-associated mortality worldwide. Therapy for gastric cancer remain largely suboptimal making the identification of novel therapeutic targets an urgent medical need. In the present study we have carried out a high-throughput sequencing of transcriptome expression in patients with gastric cancers. Twenty-four patients, among a series of 53, who underwent an attempt of curative surgery for gastric cancers in a single center, were enrolled. Patients were sub-grouped according to their histopathology into diffuse and intestinal types, and the transcriptome of the two subgroups assessed by RNAseq analysis and compared to the normal gastric mucosa. The results of this investigation demonstrated that the two histopathology phenotypes express two different patterns of gene expression. A total of 2,064 transcripts were differentially expressed between neoplastic and non-neoplastic tissues: 772 were specific for the intestinal type and 407 for the diffuse type. Only 885 transcripts were simultaneously differentially expressed by both tumors. The per pathway analysis demonstrated an enrichment of extracellular matrix and immune dysfunction in the intestinal type including CXCR2, CXCR1, FPR2, CARD14, EFNA2, AQ9, TRIP13, KLK11 and GHRL. At the univariate analysis reduced levels AQP9 was found to be a negative predictor of 4 years survival. In the diffuse type low levels CXCR2 and high levels of CARD14 mRNA were negative predictors of 4 years survival. In summary, we have identified a group of genes differentially regulated in the intestinal and diffuse histotypes of gastric cancers with AQP9, CARD14 and CXCR2 impacting on patients’ prognosis, although CXCR2 is the only factor independently impacting overall survival.
Highlights
Gastric cancer is a highly prevalent cancer representing the fifth most frequent cancer worldwide [1,2,3]
We found an upregulation of CCL3, CCL15, both overexpressed in the stromal compartment of gastric cancer [43], CCL20, that activates the pErk1/2-pAkt signaling via CCR6 inducing EMT pathways [44], and CXCLs family (CXC1, CXCL2, CXCL5 and CXCL16), that are induced by Cox2/Pge2 or Wnt5a signaling [45, 46], and correlate with tumor malignant progression, invasiveness, gastric cancer cell migration and metastasis via the activation of CXCR2/Stat3 pathway [47,48,49,50]
In particular we found an overexpression of OSMR, the receptor of Oncostatin M which promotes gastric cancer growth and metastasis [102], ITGA3, which promotes peritoneal metastasis and correlates with poor prognosis in patients with gastric cancer [103], EFNA2, one of the members of the ephrin family that are target of WNT/beta-catenin signaling implicated in the development of carcinogenesis [104], PDGFB, whose overexpression increases the growth, invasion, and angiogenesis of gastric carcinoma cells [105], FGFR4, that regulates proliferation and anti-apoptosis during gastric cancer progression [106], and SLC2A1, that induces tumor cell proliferation and metastasis in gastric Cancer when overexpressed [107]
Summary
Gastric cancer is a highly prevalent cancer representing the fifth most frequent cancer worldwide [1,2,3]. While gastric cancer incidence has shown a trend of reduction over the last decades, gastric cancer-related mortality remains the third cause of cancer-related deaths worldwide. In Western countries, due to a lack of validated cancer screening programs, the large majority patients with gastric cancer are diagnosed in the advanced stages, greatly limiting the therapeutic options. Surgery remains the only potentially curative treatment, current evidence supports adoption of perioperative therapies to improve a patient’s survival [2]. Peritoneal metastases are the most frequent metastases detected in patients with advanced gastric cancers and the peritoneal cavity is a common site for gastric cancer recurrence following surgery [4, 5]. The presence of peritoneal carcinosis is associated to reduced survival rates and overwhelming symptoms [6, 7]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.