Theranostics 2018; 8(20):5744-5757. doi:10.7150/thno.28898 This issue

Research Paper

A Positive Feedback Loop of SLP2 Activates MAPK Signaling Pathway to Promote Gastric Cancer Progression

Wenhui Ma1,2,3,4*, Zhuoluo Xu1,2,3,4*, Yutian Wang2,3,4*, Wenyi Li2,3,4, Zhigang Wei1, Tao Chen1, Tingyu Mou1, Mingzhen Cheng2,3,4, Jun Luo1, Tingyue Luo1,2,3,4, Yuehong Chen1,2,3,4, Jiang Yu1,2✉, Weijie Zhou2,3,4✉, Guoxin Li1,4✉

1. Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
2. Departments of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, China
3. Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
4. Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
*Wenhui Ma, Zhuoluo Xu and Yutian Wang contributed equally.

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Citation:
Ma W, Xu Z, Wang Y, Li W, Wei Z, Chen T, Mou T, Cheng M, Luo J, Luo T, Chen Y, Yu J, Zhou W, Li G. A Positive Feedback Loop of SLP2 Activates MAPK Signaling Pathway to Promote Gastric Cancer Progression. Theranostics 2018; 8(20):5744-5757. doi:10.7150/thno.28898. Available from https://www.thno.org/v08p5744.htm

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Abstract

Graphic abstract

Rationale: This study is to validate the clinicopathologic significance and potential prognostic value of SLP2 in gastric cancer (GC), to investigate the biological function and regulation mechanism of SLP2, and to explore potential therapeutic strategies for GC.

Methods: The expression of SLP2 in GC tissues from two cohorts was examined by IHC. The biological function and regulation mechanism of SLP2 and PHB was validated via loss-of-function or gain-of-function experiments. In vitro proliferation detection was used to evaluate the therapeutic effects of Sorafenib.

Results: We validated that SLP2 was significantly elevated in GC tissues and its elevation was associated with poor prognosis of patients. Loss of SLP2 drastically suppressed the proliferation of GC cells and inhibited the tumor growth, while SLP2 overexpression promoted the progression of GC. Mechanistically, SLP2 competed against E3 ubiquitin ligase SKP2 to bind with PHB and stabilized its expression. Loss of SLP2 significantly suppressed phosphorylation of Raf1, MEK1/2, ERK1/2 and ELK1. Furthermore, phosphorylated ELK1 could in turn activate transcription of SLP2. Finally, we demonstrated that a Raf1 inhibitor, Sorafenib, was sufficient to inhibit the proliferation of GC cells.

Conclusion: Our findings demonstrated a positive feedback loop of SLP2 which leads to acceleration of tumor progression and poor survival of GC patients. This finding also provided evidence for the reason of SLP2 elevation. Moreover, we found that sorafenib might be a potential therapeutic drug for GC and disrupting the interaction between SLP2 and PHB might also serve as a potential therapeutic target in GC.

Keywords: gastric cancer, SLP2, PHB, ELK1, positive feedback loop.