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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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          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.

          Related collections

          Most cited references 19

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          Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines.

          Small-molecule inhibitors of poly (ADP-ribose) polymerase (PARP) have shown considerable promise in the treatment of homologous recombination (HR)-defective tumors, such as BRCA1- and BRCA2-deficient breast and ovarian cancers. We previously reported that mantle cell lymphoma cells with deficiency in ataxia telangiectasia mutated (ATM) are sensitive to PARP-1 inhibitors in vitro and in vivo. Here, we report that PARP inhibitors can potentially target ATM deficiency arising in a solid malignancy. We show that ATM protein expression varies between gastric cancer cell lines, with NUGC4 having significantly reduced protein levels. Significant correlation was found between ATM protein expression and sensitivity to the PARP inhibitor olaparib, with NUGC4 being the most sensitive. Moreover, reducing ATM kinase activity using a small-molecule inhibitor (KU55933) or shRNA-mediated depletion of ATM protein enhanced olaparib sensitivity in gastric cancer cell lines with depletion or inactivation of p53. Our results demonstrate that ATM is a potential predictive biomarker for PARP-1 inhibitor activity in gastric cancer harboring disruption of p53, and that combined inhibition of ATM and PARP-1 is a rational strategy for expanding the utility of PARP-1 inhibitors to gastric cancer with p53 disruption.
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            Survivin study: what is the next wave?

             Fengzhi Li (2003)
            Survivin, a novel member of inhibitor of apoptosis (IAP) protein family, is aberrantly expressed in cancer but undetectable in normal, differentiated adult tissues. Current studies suggest that survivin is implicated in both control of apoptosis and regulation of cell division. However, due to some inconsistent observations on survivin subcellular localization, there is debate about survivin's function in regulating apoptosis, cell division, or both. This review will discuss concepts, experimental methods, and interesting results that unify the different notions about survivin localization and function or point out gaps of knowledge about controversial issues. The author also intends to review various aspects of survivin studies, which were not emphasized or sufficiently discussed in previous reviews on survivin, and update recent developments that may reveal new applications of disease-oriented therapeutics in the coming years. Copyright 2003 Wiley-Liss, Inc.
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              LKB1; linking cell structure and tumor suppression.

               A Hezel,  N Bardeesy (2008)
              Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-beta signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                OncoTargets and Therapy
                OncoTargets and therapy
                Dove Medical Press
                1178-6930
                2019
                22 February 2019
                : 12
                : 1439-1445
                Affiliations
                [1 ]Department of Oncology, The First People’s Hospital of Tianmen City, Hubei, China
                [2 ]Department of Gastrointestinal Surgery, The First People’s Hospital of Tianmen City, Hubei, China
                [3 ]Department of Pathology, The First People’s Hospital of Tianmen City, Hubei, China, linwang0110@ 123456163.com
                Author notes
                Correspondence: Lin Wang, Department of Pathology, The First People’s Hospital of Tianmen City, 1# Renmin Road, Tianmen 431700, Hubei, China, Tel +86 180 6429 6932, Email linwang0110@ 123456163.com
                Article
                ott-12-1439
                10.2147/OTT.S199138
                6390856
                © 2019 Li et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Oncology & Radiotherapy

                gastric cancer, liver kinase b1, p53, survivin, prognosis

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