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

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.

原理：本研究旨在验证SLP2在胃癌（GC）中的临床病理意义和潜在预后价值，探究SLP2的生物学功能和调控机制，并探索胃癌的潜在治疗策略。 方法：通过免疫组化（IHC）检测两个队列胃癌组织中SLP2的表达。通过功能缺失或功能获得实验验证SLP2和 prohibitin（PHB）的生物学功能和调控机制。采用体外增殖检测评估索拉非尼的治疗效果。 结果：我们证实SLP2在胃癌组织中显著升高，且其升高与患者预后不良相关。SLP2缺失显著抑制胃癌细胞增殖并抑制肿瘤生长，而SLP2过表达促进胃癌进展。从机制上讲，SLP2与E3泛素连接酶SKP2竞争结合PHB并稳定其表达。SLP2缺失显著抑制Raf1、MEK1/2、ERK1/2和ELK1的磷酸化。此外，磷酸化的ELK1反过来可激活SLP2的转录。最后，我们证明一种Raf1抑制剂索拉非尼足以抑制胃癌细胞增殖。 结论：我们的研究结果表明存在一个SLP2的正反馈回路，它导致肿瘤进展加速和胃癌患者生存不良。这一发现也为SLP2升高的原因提供了证据。此外，我们发现索拉非尼可能是一种潜在的胃癌治疗药物，破坏SLP2和PHB之间的相互作用也可能作为胃癌的一个潜在治疗靶点。