Short-form RON (sf-RON) enhances glucose metabolism to promote cell proliferation via activating \u03b2-catenin/SIX1 signaling pathway in gastric cancer

Ziliang Wang,Jian He,Midie Xu,Shuang Hu,Rujiao Liu,Zihao Qi,Yufei Yang,Ying Lin,Zhe Zhang,Zheng Wu,Mingzhu Huang,Cong Tan

doi:10.1007/s10565-020-09525-5

Abstract

Recepteur d’origine nantais (RON) has been implicated in cell proliferation, metastasis, and chemoresistance of various human malignancies. The short-form RON (sf-RON) encoded by RON transcripts was overexpressed in gastric cancer tissues, but its regulatory functions remain illustrated. Here, we found that sf-RON promoted gastric cancer cell proliferation by enhancing glucose metabolism. Furthermore, sf-RON was proved to induce the β-catenin expression level through the AKT1/GSK3β signaling pathway. Meanwhile, the binding sites of β-catenin were identified in the promoter region of SIX1 and it was also demonstrated that β-catenin positively regulated SIX1 expression. SIX1 enhanced the promoter activity of key proteins in glucose metabolism, such as GLUT1 and LDHA. Results indicated that sf-RON regulated the cell proliferation and glucose metabolism of gastric cancer by participating in a sf-RON/β-catenin/SIX1 signaling axis and had significant implications for choosing the therapeutic target of gastric cancer.

Highlights

Gastric carcinoma (GC) is one of the most common gastrointestinal cancers and ranks a third cause of cancer-related death worldwide (Siegel et al 2020)
39 had been undergone preoperative positron emission tomography/ computed tomography (PET/CT) scan, and we found that 26 patients only belonged to the short-form Recepteur d’origine nantais (RON) (sf-RON) group, and 13 patients only belonged to the RON group
We compared the metabolic activity of each lesion by analyzing the maximum standardized uptake value (SUVmax) and found that patients of RON group showed significantly lower SUVmax values than those in sf-RON group (P = 0.023, Fig. 1b), which indicates that compared with RON, sf-RON might have more close correlation with glucose metabolism in gastric patients

Summary

Introduction

Gastric carcinoma (GC) is one of the most common gastrointestinal cancers and ranks a third cause of cancer-related death worldwide (Siegel et al 2020). Considerable attention was paid to early screening and surgical techniques, patient mortality, due to recurrence, metastasis, and chemotherapy resistance, remains high (Van Cutsem et al 2016; Necula et al 2019). The development of early diagnosis maker, as well as therapeutic target, remains an ongoing challenge and it is worthwhile devoting much effort to this area. Aerobic glycolysis (Warburg effect) is a biochemical fingerprint of cancer cells that represents one of the “hallmarks of cancer.”. It is a much more inefficient way for ATP production compared to oxidative phosphorylation, this rapidly satisfies the energy requirement of cancer cells for quick proliferation (Sun et al 2018). Cumulative evidence supported gastric cancer as a metabolic disease and pointed out that

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