Prognostic significance and function of phosphorylated ribosomal protein S6 in esophageal squamous cell carcinoma

Abstract

Ribosomal protein S6 is a key regulator of 40S ribosome biogenesis, and its phosphorylation is closely related to cell growth capacity. However, as a downstream target of S6 kinases, the clinical significance and the roles of S6 and S6 phosphorylation in cell viability and motility of esophageal squamous cell carcinoma remain unclear. Here, we show that high level of phosphorylated-ribosomal protein S6 (p-S6) (immunohistochemistry score Z5) and an increased ratio of p-S6/S6 (immunohistochemistry score Z0.75) were significantly associated with shortened disease-free survival in patients with esophageal squamous cell carcinoma in univariate analysis (P ¼ 0.049 and Po0.001, respectively). After adjusting for age, tumor-nodes-metastasis stage, chemotherapy, and radiation therapy in multivariate analysis, both p-S6 (hazard ratio 2.21, P ¼ 0.005) and p-S6/S6 (hazard ratio 2.40, Po0.001) remained independent adverse prognostic factors. In addition, S6 and S6 kinase 1 knockdown resulted in attenuation of viability by suppressing cyclin D1 expression in esophageal cancer cells. Furthermore, depletion of S6 and S6 kinase 1 resulted in a reduction in esophageal cancer cell migration and invasion. This was paralleled by a reduction in focal adhesion and by suppression of extracellular signal-regulated kinase and c-jun N-terminal kinase phosphorylation, which control cell motility. Collectively, these findings suggest that p-S6 and the ratio of p-S6/S6 are closely relevant to tumor progression and have prognostic significance in esophageal squamous cell carcinoma. Modern Pathology (2013) 26, 327-335; doi:10.1038/modpathol.2012.161; published online 21 September 2012Keywords: esophagus squamous cell carcinoma; phosphorylation; S6 Esophageal squamous cell carcinoma is one of the most aggressive malignant tumors of the gastrointestinal tract, and has a high mortality rate. 1 The prognosis of esophagus squamous cell carcinoma is poor due to a high incidence of metastasis to lymph nodes, liver, and lung. 1 Despite the development of multimodal therapies including surgery, chemotherapy, radiotherapy, and chemo-radiotherapy, the 5-year survival rate of patients remains in the range of 10 to 25%, 1 underscoring the need for identifying the signaling pathways and downstream targets that lead to esophageal cancer progression and metastasis. 2,3 Recently, the mammalian target of rapamycin (mTOR)-S6 kinase (S6K1) signaling pathway-has emerged as a critical regulator of cellular metabolism, proliferation, and survival in response to growth factor and nutrient availability. [4][5][6][7] Upon growth factor stimulation, mTOR-dependent activation of S6K1 induces phosphorylation of S6, the 40S ribosomal protein at Ser235, Ser236, Ser240, Ser244, and Ser247. 8,9 The importance of S6 phosphorylation is underscored by the finding that mouse embryonic fibroblasts from S6 knock-in mice in which all phosphorylatable serine residues in S6 are substituted by alanines exhibit small cell size, 10 indicating the potential role of S6 phosphorylation in r...

Retracted: Ribosomal Protein S15A Augments Human Osteosarcoma Cell Proliferation In Vitro

“…RPS6 knockdown resulted in a reduction in esophageal cancer cell growth, migration, and invasion, and cyclin D1 is involved in the process. 25 More importantly, Montanaro and his colleagues have proved that the actinomycin D treatment, an inhibitor of ribosome biogenesis, induces a cell cycle arrest in U2OS cells. 26 This was in accordance with the data showing that RPS15A inhibition arrested U2OS cells at the G0/G1 phase.…”

Ribosomal protein S15A promotes malignant transformation and predicts poor outcome in colorectal cancer through misregulation of p53 signaling pathway

“…Ribosomal protein S6 (RPS6), a key regulator of 40S ribosome biogenesis, actively participates in human esophageal cancer progression. RPS6 knockdown resulted in a reduction in esophageal cancer cell growth, migration and invasion (17).…”

The role of ribosomal proteins in the regulation of cell proliferation, tumorigenesis, and genomic integrity

“…(Fatima et al, 2012;Ganger et al, 2001;Kim et al, 2004;Masuda et al, 2014;Song et al, 2011) Esophageal cancer p-S6, L15 Upregulation Downregulation of L14 occurs frequently in ESCC and is an early event in the tumorigenesis of the esophagus. Kim et al, 2013;Wang et al, 2001) L14 Downregulation…”