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      Role of serine/threonine kinase 33 methylation in colorectal cancer and its clinical significance

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          Abstract

          Serine/threonine kinase 33 (STK33) is a novel protein that has been the focus of an increasing number of studies in recent years; however, the role of STK33 in tumorigenesis remains controversial. Previous studies have demonstrated that STK33 is overexpressed in several human cancers and exerts a pro-tumorigenic effect through the promotion of cell proliferation. However, the role of STK33 in colorectal cancer (CRC), which is one of the most aggressive human malignancies, remains unclear. The aim of the current study was to investigate the methylation status of STK33 in CRC and to determine its clinical significance. The results demonstrated that STK33 was hypermethylated in CRC cell lines and promoted the proliferation of CRC cells. In addition, the methylation status and expression of STK33 in 94 pairs of cancer and noncancerous tissues obtained from patients with CRC was investigated. STK33 methylation was significantly increased in cancer tissues when compared with adjacent noncancerous tissues (P<0.001). STK33 methylation was associated with lymph node metastasis (P<0.05), tumor invasion (P<0.05), distant metastases (P<0.01) and tumor stage (P<0.01). Reduced STK33 mRNA and protein expression in CRC was associated with STK33 hypermethylation (P<0.001). In addition, patients with hypermethylated STK33 exhibited shorter overall survival rates when compared with those with unmethylated STK33 (P<0.01). In conclusion, the results of the current study suggest that STK33 hypermethylation may be a promising novel biomarker for the diagnosis, prognosis and suitable treatment of CRC.

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          Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells.

          An alternative to therapeutic targeting of oncogenes is to perform "synthetic lethality" screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with "undruggable" genetic alterations.
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            Cancer trends in China.

            Cancer is the leading death cause in urban China and the second one in rural China. Lung cancer is the most common cancer, followed by stomach cancer, liver cancer, esophageal cancer and colorectal cancer. Cancer Control Programs in China focus on prevention, early diagnosis and treatment. The prevention program includes an anti-smoking campaign and immunization against hepatitis B for infants and children under the age of 15. Screening for breast and cervix cancers is among efforts for the early detection and treatment. Public education and the promotion of healthy lifestyles have been actively carried out.
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              AJCC Cancer Staging Manual

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                Author and article information

                Journal
                Oncol Lett
                Oncol Lett
                OL
                Oncology Letters
                D.A. Spandidos
                1792-1074
                1792-1082
                February 2018
                14 December 2017
                14 December 2017
                : 15
                : 2
                : 2153-2160
                Affiliations
                Department of Colon and Rectum Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, P.R. China
                Author notes
                Correspondence to: Dr Si-Ping Ma, Department of Colon and Rectum Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Dadong, Shenyang, Liaoning 110042, P.R. China, E-mail: siping_ma@ 123456yeah.net
                Article
                OL-0-0-7614
                10.3892/ol.2017.7614
                5776884
                29434919
                df90ec03-3c99-4130-a260-21801fed1713
                Copyright: © Yin et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 06 July 2016
                : 07 November 2017
                Categories
                Articles

                Oncology & Radiotherapy
                serine/threonine kinase 33,methylation,colorectal cancer,prognostic,calcium/calmodulin-dependent kinase

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