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Impact of liver kinase B1 on p53 and survivin and its correlation with prognosis in gastric cancer.

ABSTRACT: Background:Liver kinase B1 (LKB1) is a newly discovered tumor suppressor gene that plays a role in apoptosis induction. However, the precise impact of LKB1 expression on gastric cancer (GC) progression and its correlation with survivin and p53 in GC have not yet been elucidated. Purpose:The aim of this study was to explore the significance of LKB1 expression and its correlation with p53 and survivin in GC. Patients and methods:In this study, LKB1 expression was detected in GC and adjacent paracancerous tissues from 150 patients through immunohistochemical (IHC) staining. The relationship between LKB1 expression and clinical pathological factors in GC was analyzed, alongside its correlation with p53 and survivin expression. Results:LKB1 expression was reduced in GC tissues compared with adjacent paracancerous tissues (P=0.001). In patients with GC, lower LKB1 expression was associated with greater invasion depth (P=0.013), higher pTNM stage (P=0.009), and lymph node metastasis (P=0.029). Furthermore, LKB1 expression in GC was inversely associated with p53 (r=-0.181, P=0.027) and survivin expression (r=-0.198, P=0.015). Kaplan-Meier analysis indicated that the expression of LKB1, p53 and survivin, as well as tumor differentiation, invasion, and pTNM and lymph node metastasis were all associated with overall survival (OS) (all P<0.05). Finally, multivariate analysis showed that LKB1 expression [hazard ratio (HR): 0.605 (0.414-0.882), P=0.009], p53 expression [hazard ratio (HR): 1.840 (1.232-2.750), P=0.003], and survivin expression [hazard ratio (HR): 1.561 (1.039-2.345), P=0.032] were all independent prognostic factors for patients with GC. Conclusion:Our study suggests that LKB1 expression is reduced in GC, negatively correlated with p53 and survivin expression, and plays an important role in predicting invasion and metastasis of GC.

SUBMITTER: Li W

PROVIDER: S-EPMC6390856 | biostudies-other | 2019

REPOSITORIES: biostudies-other

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Impact of liver kinase B1 on p53 and survivin and its correlation with prognosis in gastric cancer.

Li Weiwei W Luo Shunxiang S Ma Guowei G Wang Lin L

OncoTargets and therapy 20190222

<h4>Background</h4>Liver kinase B1 (LKB1) is a newly discovered tumor suppressor gene that plays a role in apoptosis induction. However, the precise impact of LKB1 expression on gastric cancer (GC) progression and its correlation with survivin and p53 in GC have not yet been elucidated.<h4>Purpose</h4>The aim of this study was to explore the significance of LKB1 expression and its correlation with p53 and survivin in GC.<h4>Patients and methods</h4>In this study, LKB1 expression was detected in ...[more]

PMID: 30863111

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Project description:Aurora kinase A (AURKA) has been implicated in the regulation of cell cycle progression, mitosis and a key number of oncogenic signaling pathways in various malignancies. However, little is known about its role in gastric cancer prognosis and genotoxic resistance. Here we found that AURKA was highly overexpressed in gastric cancer and inversely correlated with disease prognosis. Overexpression of AURKA exacerbated gastric cancer drug resistance through upregulating the expression of the anti-apoptotic protein Survivin. Conversely, we demonstrated that AURKA depletion caused a decrease in Survivin protein levels by increasing its ubiquitylation and degradation. Mass spectrometric analysis revealed that upon AURKA depletion, Survivin bound to the FBXL7 E3 ubiquitin ligase, which induced ubiquitin-proteasome degradation of Survivin. In addition, we showed that AURKA regulated FBXL7 both at the levels of transcription and translation. Moreover, proteomic analysis of nuclear AURKA-interacting proteins identified Forkhead box protein P1 (FOXP1). We next showed that AURKA was required for FBXL7 transcription and that AURKA negatively regulated FOXP1-mediated FBXL7 expression. The physiological relevance of the regulation of Survivin by AURKA through the FOXP1-FBXL7 axis was further underscored by the significant positive correlations between AURKA and Survivin expression in gastric cancer patient samples. Moreover, the AURKA depletion or kinase inhibition-induced apoptotic cell death could be reversed by Survivin ectopic overexpression, further supporting that AURKA regulated Survivin to enhance drug resistance. In agreement, inhibition of AURKA synergistically enhanced the cytotoxic effect of DNA-damaging agents in cancer cells by suppressing Survivin expression. Taken together, our data suggest that AURKA restricts Survivin ubiquitylation and degradation in gastric cancer to promote drug resistance and hence the AURKA-Survivin axis can be targeted to promote the efficacy of DNA-damaging agents in gastric cancer.

Project description:BackgroundGastric cancer (GC) is a malignancy with high morbidity/mortality, partly due to a lack of reliable biomarkers for early diagnosis. It is important to develop reliable biomarker(s) with specificity, sensitivity and convenience for early diagnosis. The role of tumour-associated macrophages (TAMs) and survival of GC patients are controversial. Macrophage colony stimulating factor (MCSF) regulates monocytes/macrophages. Elevated MCSF is correlated with invasion, metastasis and poor survival of tumour patients. IL-34, a ligand of the M-CSF receptor, acts as a "twin" to M-CSF, demonstrating overlapping and complimentary actions. IL-34 involvement in tumours is controversial, possibly due to the levels of M-CSF receptors. While the IL-34/M-CSF/M-CSFR axis is very important for regulating macrophage differentiation, the specific interplay between these cytokines, macrophages and tumour development is unclear.MethodsA multi-factorial evaluation could provide more objective utility, particularly for either prediction and/or prognosis of gastric cancer. Precision medicine requires molecular diagnosis to determine the specifically mutant function of tumours, and is becoming popular in the treatment of malignancy. Therefore, elucidating specific molecular signalling pathways in specific cancers facilitates the success of a precision medicine approach. Gastric cancer tissue arrays were generated from stomach samples with TNM stage, invasion depth and the demography of these patients (n = 185). Using immunohistochemistry/histopathology, M-CSF, IL-34 and macrophages were determined.ResultsWe found that IL-34 may serve as a predictive biomarker, but not as an independent, prognostic factor in GC; M-CSF inversely correlated with survival of GC in TNM III-IV subtypes. Increased CD68+ TAMs were a good prognostic factor in some cases and could be used as an independent prognostic factor in male T3 stage GC.ConclusionOur data support the potency of IL-34, M-CSF, TAMs and the combination of IL-34/TAMs as novel biological markers for GC, and may provide new insight for both diagnosis and cellular therapy of GC.

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Impact of liver kinase B1 on p53 and survivin and its correlation with prognosis in gastric cancer.

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Impact of liver kinase B1 on p53 and survivin and its correlation with prognosis in gastric cancer.

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