Ceramide synthase 6 predicts the prognosis of human gastric cancer: It functions as an oncoprotein by dysregulating the SOCS2/JAK2/STAT3 pathway

Abstract

Although gastric cancer (GC) is one of the most common cancers, knowledge of its development, and carcinogenesis is limited. The present study explored the involvement of ceramide synthase 6 (CERS6) in GC carcinogenesis and prognosis. RT-PCR, immunoblotting, and immunohistochemistry were used to examine the expression of CERS6. Transfection and small hairpin RNA technology were used to investigate the effect of CERS6 manipulation on cell proliferation and spread as well as the underlying mechanism. Moreover, xenograft proliferation was employed to explore the influence of CERS6 on tumor growth in animals. It was found that overexpression of CERS6 was significantly correlated with several clinicopathologic parameters and poor disease-free survival. The overexpression and silencing of CERS6 in GC cells facilitated and suppressed cell proliferation and spread as well as xenograft proliferation, respectively. Mechanistic studies further revealed that CERS6 influenced cell proliferation and spread by regulating cell cycle control and metastasis-related protein through the SOCS2/JAK2/STAT3 signaling pathway. Collectively, this study suggests that CERS6 overexpression could be a useful biomarker for predicting the outcomes of GC patients and that CERS6 targeting represents a potential modality for treating GC.

The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy

“…C16-ceramide induced apoptosis through BAX in HeLa cells following irradiation, and C16-ceramide also activated caspase 3 translocation to the nucleus resulting in increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity in colon cancer cells [85,86]. Paradoxically, C16-ceramide was found elevated in oral and gastric cancer [64,87,88]. CerS6 overexpression has been described as a biomarker in gastric cancer, and CerS6 overexpression was associated with poor patient survival, invasion, and metastasis in gastric cancer [88].…”

Ubiquitin-specific protease 3 promotes cell migration and invasion by interacting with and deubiquitinating SUZ12 in gastric cancer

“…GC metastasis, which is responsible for almost 90% of the lethality among GC patients, is a multistep process that results from alterations in genes, including the activation of oncogenes and the inactivation and mutation of tumor suppressor genes [2]. Through greater awareness, earlier detection, and advances in treatment, the survival of GC patients has improved; however, a proportion of patients will eventually succumb to the disease as a result of metastasis [3]. Therefore, the identification of novel genes and the discovery of the detailed mechanisms underlying GC metastasis are urgently needed.…”

Ubiquitin‐specific protease 3 overexpression promotes gastric carcinogenesis and is predictive of poor patient prognosis

“…Some studies have indicated that dysregulation of protein and RNA expression may play a crucial role in the development of GC . Several molecules that can be used as prognostic biomarkers for GC include EPAC1, MFN2, CDKL2, CerS6, BMI1, Mel‐18, miR‐429 and miR‐1225‐5p …”

“…5,6 Several molecules that can be used as prognostic biomarkers for GC include EPAC1, MFN2, CDKL2, CerS6, BMI1, Mel-18, miR-429 and miR-1225-5p. [7][8][9][10][11][12][13] The ubiquitin-proteasome system has many critical regulatory roles in eukaryotic cellular processes, including cell cycle progression, stress response, and signal transduction. [14][15][16] Protein ubiquitination is both dynamic and reversible.…”