Suppression of SHIP2 contributes to tumorigenesis and proliferation of gastric cancer cells via activation of Akt

Yan, Ye; Ge, Yan; Xiao, Meihua; Guo, Li; Li, Qun; Hao, Ji Qing; Da, Jie; Wang, Hu; Zhang, Xu Dong; Xu, Jiegou; Zhang, Lin Jie

doi:10.1007/s00535-015-1101-0

Cited by 38 publications

(51 citation statements)

References 36 publications

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“…SH2‐containing inositol 5‐phosphatase 2 (SHIP2) has been reported to negatively regulate PI3K/Akt signaling and suppress cancer progression in glioblastoma, prostate cancer, osteosarcoma and gastric cancer . In contrast, increasing evidence suggests that SHIP2 also plays a protumorigenic role in some types of human cancer .…”

Section: Discussionmentioning

confidence: 99%

PLEK2 mediates metastasis and vascular invasion via the ubiquitin‐dependent degradation of SHIP2 in non‐small cell lung cancer

Deng

Zhou³

et al. 2019

Intl Journal of Cancer

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Metastasis is the leading cause of death for non‐small cell lung cancer (NSCLC) patients. However, how lung cancer cells invade blood vessels during metastasis remains unclear. Here, based on bioinformatics analyses, we found that PLEK2 might regulate NSCLC migration and vascular invasion. As little is known about the function of PLEK2 in NSCLC, we aimed to clarify this. We demonstrated that PLEK2 was significantly upregulated in transforming growth factor beta 1 (TGF‐β1)‐treated NSCLC cells through ELK1 transcriptional activation, highly expressed in NSCLC tissues, and negatively correlated with NSCLC overall survival. Meanwhile, PLEK2 overexpression significantly promoted NSCLC epithelial‐to‐mesenchymal transition (EMT) and migration, human lung microvascular endothelial cells endothelial‐to‐mesenchymal transition (EndoMT), and the destruction of vascular endothelial barriers. Moreover, PLEK2 knockdown inhibited TGF‐β1‐induced EMT and EndoMT. Furthermore, PLEK2 was found to directly interact with SHIP2 and target it for ubiquitination and degradation in NSCLC cells. Next, we confirmed that SHIP2 overexpression inhibits NSCLC EMT, migration and invasion and showed that PLEK2 overexpression can activate SHIP2‐associated TGF‐β/PI3K/AKT signaling. Our results suggest that PLEK2 could be a novel prognostic marker and potential therapeutic target for NSCLC metastasis and vascular invasion.

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Section: Discussionmentioning

confidence: 99%

PLEK2 mediates metastasis and vascular invasion via the ubiquitin‐dependent degradation of SHIP2 in non‐small cell lung cancer

Deng

Zhou³

et al. 2019

Intl Journal of Cancer

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“…Baicalin dose-dependently inhibited vascular smooth muscle cell proliferation by blocking the ERK pathway (33). Activation of the AKT pathway contributes to the proliferation of gastric cancer (34) and cervical cancer cells (35). Curcumin was found to play an anticancer role by suppressing AKT phosphorylation (36).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen sulfide promotes cell proliferation of oral cancer through activation of the COX2/AKT/ERK1/2 axis

Zhang

Bian

et al. 2016

Oncology Reports

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Hydrogen sulfide, the third gaseous transmitter, is one of the main causes of halitosis in the oral cavity. It is generally considered as playing a deleterious role in many oral diseases including oral cancer. However, the regulatory mechanisms involved in the effects of hydrogen sulfide on oral cancer growth remain largely unknown. In the present study, we investigated the underlying mechanisms through CCK-8 assay, EdU incorporation, real-time PCR, western blot and pathway blockade assays. Our results showed that hydrogen sulfide promoted oral cancer cell proliferation through activation of the COX2, AKT and ERK1/2 pathways in a dose-dependent manner. Blocking any of the three above pathways inhibited hydrogen sulfide-induced oral cancer cell proliferation. Meanwhile, blockade of COX2 by niflumic acid downregulated NaHS-induced p-ERK and p-AKT expression. Inactivation of the AKT pathway by GSK690693 significantly decreased NaHS‑induced p-ERK1/2 expression, and inhibition of the ERK1/2 pathway by U0126 markedly increased NaHS-induced p-AKT expression. Either the AKT or ERK1/2 inhibitor did not significantly alter the COX2 expression level. Our data revealed, for the first time, that hydrogen sulfide promotes oral cancer cell proliferation through activation of the COX2/AKT/ERK1/2 axis, suggesting new potential targets to eliminate the effect of hydrogen sulfide on the development of oral cancer.

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“…Beneficial effects of SHIP2 inhibition have been proposed in breast and colorectal cancer . In gastric cancer specimens, however, SHIP2 expression is frequently downregulated, and this enhances the malignant behaviour of gastric cancer cells . Accordingly, it appears that the effects of SHIP2 in different cells are context dependent.…”

Section: Benefits and Caveats Of Inhibiting Ship2mentioning

confidence: 99%

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

Lehtonen

2019

Acta Physiologica

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SHIP2 (Src homology 2 domain‐containing inositol 5′‐phosphatase 2) belongs to the family of 5′‐phosphatases. It regulates the phosphoinositide 3‐kinase (PI3K)‐mediated insulin signalling cascade by dephosphorylating the 5′‐position of PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2, suppressing the activity of the pathway. SHIP2 mouse models and genetic studies in human propose that increased expression or activity of SHIP2 contributes to the pathogenesis of the metabolic syndrome, hypertension and type 2 diabetes. This has raised great interest to identify SHIP2 inhibitors that could be used to design new treatments for metabolic diseases. This review summarizes the central mechanisms associated with the development of diabetic kidney disease, including the role of insulin resistance, and then moves on to describe the function of SHIP2 as a regulator of metabolism in mouse models. Finally, the identification of SHIP2 inhibitors and their effects on metabolic processes in vitro and in vivo are outlined. One of the newly identified SHIP2 inhibitors is metformin, the first‐line medication prescribed to patients with type 2 diabetes, further boosting the attraction of SHIP2 as a treatment target to ameliorate metabolic disorders.

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Suppression of SHIP2 contributes to tumorigenesis and proliferation of gastric cancer cells via activation of Akt

Abstract: This study demonstrates, for the first time, that SHIP2 is frequently downregulated in gastric cancer, and reduced SHIP2 expression promotes tumorigenesis and proliferation of gastric cancer via activation of the PI3K/Akt signaling.

Cited by 38 publications

References 36 publications

PLEK2 mediates metastasis and vascular invasion via the ubiquitin‐dependent degradation of SHIP2 in non‐small cell lung cancer

PLEK2 mediates metastasis and vascular invasion via the ubiquitin‐dependent degradation of SHIP2 in non‐small cell lung cancer

Hydrogen sulfide promotes cell proliferation of oral cancer through activation of the COX2/AKT/ERK1/2 axis

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

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