Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer

Li, Xinran; Mak, Victor; Zhou, Yuan; Wang, Chao; Wong, Eric T.T.; Sharma, Rakesh; Lu, Yiling; Cheung, Annie N. Y.; Mills, Gordon B.; Cheung, Lydia W.T.

doi:10.1038/s41467-019-08574-7

Cited by 40 publications

(38 citation statements)

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“…PIK3R1 has been identified to be differentially expressed in many human cancers. For example, PIK3R1 functions as a tumor suppressor in hepatocellular carcinomas and renal cancer [27,28], whereas acts as an oncogene in ovarian and colon tumors and plays a role in tumor progression and metastasis [29,30]. However, the relationship between PIK3R1 and LSCC cell development has not been fully elucidated.…”

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confidence: 99%

Silencing of miR-17-5p suppresses cell proliferation and promotes cell apoptosis by directly targeting PIK3R1 in laryngeal squamous cell carcinoma

et al. 2020

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Background: Increasing evidence has suggested that microRNAs (miRNAs) act as key post-transcriptional regulators in tumor progression. Previous studies have confirmed that miR-17-5p functions as an oncogene in multiple cancers and contributes to tumor progression. However, the role and biological functions of miR-17-5p in the development of laryngeal squamous cell carcinoma (LSCC) still remain unknown.Methods: qRT-PCR was used to detect miRNA and mRNA expression levels in LSCC tissues and cell lines. CCK-8 assay was used to measure cell viability and flow cytometry was performed to evaluate cell apoptosis. Western blot analysis was used to detect the protein levels of BAX, BCL-2, cleaved Caspase-3, PIK3R1 and AKT. Luciferase reporter assay was used to detect the effect of miR-17-5p on PIK3R1 expression. Xenograft animal model was used to test the effect of miR-17-5p on LSCC cell in vivo. Results:In the present study, we found that miR-17-5p expression level was upregulated in LSCC tissues and cell lines. Depletion of miR-17-5p in LSCC cells significantly reduced cell proliferation and promoted cell apoptosis in vitro and in vivo. Mechanically, knockdown of miR-17-5p in LSCC cells inhibited BCL-2 expression while enhanced BAX and cleaved Caspase-3 protein expression. Moreover, depletion of miR-17-5p in LSCC cells suppressed AKT phosphorylation but did not influence PTEN expression. Importantly, miR-17-5p positively regulated PIK3R1 expression by directly binding to its 3′-untranslated region (UTR). Additionally, PIK3R1, which expression was downregulated in LSCC tissues and cell lines, was involved in LSCC cell survival by modulating the activation of AKT signal pathway. Dysregulation of miR-17-5p/PIK3R1 axis was participated in LSCC cell proliferation and apoptosis by inhibiting the activation of the PI3K/AKT signaling pathway. Conclusions:In conclusion, our study indicates that the miR-17-5p/PIK3R1 axis plays an essential role in the development of LSCC and provides a potential therapeutic target for LSCC treatment. BackgroundLaryngeal squamous cell carcinoma (LSCC) is the most common head and neck malignancy accounting for more than 95% of head and neck squamous cell carcinoma (HNSCC), with 177,422 new cases and 94,771

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Silencing of miR-17-5p suppresses cell proliferation and promotes cell apoptosis by directly targeting PIK3R1 in laryngeal squamous cell carcinoma

et al. 2020

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“…Although there is functional specificity among p110 isoforms 1,2 , the roles of p85 isoforms in cancers are only beginning to be understood. PIK3R1 (encodes p85α) has been suggested to act as a tumor suppressor through functions such as inhibiting p110 kinase activity and stabilizing phosphatase and tensin homolog (PTEN) 3,4 . Depletion of p85α can thus lead to enhanced p110 activity and PTEN destabilization, as well as cell context-dependent activation of oncogenic signaling [3][4][5] .…”

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confidence: 99%

“…PIK3R1 (encodes p85α) has been suggested to act as a tumor suppressor through functions such as inhibiting p110 kinase activity and stabilizing phosphatase and tensin homolog (PTEN) 3,4 . Depletion of p85α can thus lead to enhanced p110 activity and PTEN destabilization, as well as cell context-dependent activation of oncogenic signaling [3][4][5] . Indeed, loss-of-function disruptions in PIK3R1 are frequent in cancers, including copy number loss and truncation or point mutations.…”

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confidence: 99%

p85β regulates autophagic degradation of AXL to activate oncogenic signaling

et al. 2020

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PIK3R2 encodes the p85β regulatory subunit of phosphatidylinositol 3-kinase and is frequently amplified in cancers. The signaling mechanism and therapeutic implication of p85β are poorly understood. Here we report that p85β upregulates the protein level of the receptor tyrosine kinase AXL to induce oncogenic signaling in ovarian cancer. p85β activates p110 activity and AKT-independent PDK1/SGK3 signaling to promote tumorigenic phenotypes, which are all abolished upon inhibition of AXL. At the molecular level, p85β alters the phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate the selective regulation of AXL by p85β, thereby disrupting the autophagic degradation of the AXL protein. Therapeutically, p85β expression renders ovarian cancer cells vulnerable to inhibitors of AXL, p110, or PDK1. Conversely, p85β-depleted cells are less sensitive to these inhibitors. Together, our findings provide a rationale for pharmacological blockade of the AXL signaling axis in PIK3R2-amplified ovarian cancer.

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“…Our findings show that the expression of both SOCS1 and SOCS3 show a high degree of mutual exclusivity with PIK3R1 ( Figure 6A). Even though this gene codes for the p85 regulatory subunit of PI3K, there is strong evidence indicating its role also as a tumor suppressor by positively modulating PTEN, a negative regulator of the PI3K pathway, and by modulating AKT and STAT3 activation [101][102][103]. Consistent with this, high PIK3R1 predicts favorable survival, whereas its lower expression in synergy with low SOCS1 predicts poor survival ( Table 2).…”

Section: Pi3k-akt-mtor Signaling Pathwaymentioning

confidence: 87%

Prognostic significance ofSOCS1andSOCS3tumor suppressors in hepatocellular carcinoma and its correlation to key oncogenic signaling pathways

Khan

Ghosh

Variya

et al. 2020

Preprint

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Suppressor of cytokine signaling (SOCS) proteins SOCS1 and SOCS3 are considered tumor suppressors in liver hepatocellular carcinoma (LIHC). To gain insight into the underlying molecular mechanisms, the expression of SOCS1/ SOCS3 was evaluated in The Cancer Genome Atlas LIHC dataset along with key oncogenic signaling pathway genes. SOCS1 expression was not significantly reduced in HCC yet higher expression predicted favorable prognosis, whereas SOCS3 lacked predictive potential despite lower expression. Only a small proportion of the cell cycle, receptor tyrosine kinase, growth factor and RAS-RAF-MEK-MAPK signaling genes negatively correlated with SOCS1 or SOCS3, of which even fewer showed elevated expression in HCC and predicted survival. However, many PI3K-AKT-MTOR pathway genes showed mutual exclusivity with SOCS1/SOCS3 and displayed independent predictive ability. Among genes that negatively correlated with SOCS1/SOCS3, CDK2, MLST8, AURKA, MAP3K4 and RPTOR showed corresponding modulations in the livers of mice lacking Socs1 or Socs3 during liver regeneration and in experimental HCC, and in Hepa1-6 murine HCC cells overexpressing SOCS1/SOCS3. However, Cox proportional hazards model identified CXCL8, DAB2 and PIK3R1 as highly predictive in combination with SOCS1 or SOCS3. These data suggest that developing prognostic biomarkers and precision treatment strategies based on SOCS1/SOCS3 expression need careful testing in different patient cohorts.Prognostic significance of SOCS1 and SOCS3 in HCC Khan et al.,3 genes that regulate hepatocyte proliferation and survival. Our findings show that the expression of SOCS1 and SOCS3 negatively correlates with several genes in a similar fashion, but also show distinct regulation of a number of genes in several oncogenic signaling pathways. The latter could explain, at least partly, the inability of SOCS3 to compensate for the loss of SOCS1 and vice versa in animal models of HCC. We identify SOCS1 but not SOCS3 as an independent prognostic factor, whereas both display improved predictive potential when combined with certain key genes of the oncogenic signaling pathways. Besides, our findings reveal important differences between published works on putative HCC biomarkers and the TCGA data, highlighting the need for further studies on prognostic biomarkers for precision HCC therapy.

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Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer

Cited by 40 publications

References 54 publications

Silencing of miR-17-5p suppresses cell proliferation and promotes cell apoptosis by directly targeting PIK3R1 in laryngeal squamous cell carcinoma

Silencing of miR-17-5p suppresses cell proliferation and promotes cell apoptosis by directly targeting PIK3R1 in laryngeal squamous cell carcinoma

p85β regulates autophagic degradation of AXL to activate oncogenic signaling

Prognostic significance ofSOCS1andSOCS3tumor suppressors in hepatocellular carcinoma and its correlation to key oncogenic signaling pathways

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