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      High kinesin family member 18A expression correlates with poor prognosis in primary lung adenocarcinoma

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          Abstract

          Background

          Lung adenocarcinoma (LUAD) is the most prevalent pathological subtype of lung cancer. Kinesin family member 18A (KIF18A) plays an important role in tumorigenesis. Its roles in breast cancer, colorectal cancer, and other tumors have been demonstrated; however, studies of KIF18A in LUAD are limited. This study aimed to determine the role of KIF18A in LUAD progression and prognostic prediction.

          Methods

          KIF18A expression was examined in LUAD cells and tissues by immunohistochemistry and Western blotting. Cell proliferation assay was performed to study the role of KIF18A in LUAD cells. Correlations between KIF18A expression and clinicopathological features were analyzed. The role of KIF18A in LUAD prognosis was evaluated using data from The Cancer Genome Atlas (TCGA).

          Results

          KIF18A expression was increased in tumor cells and tissues. Downregulation of KIF18A expression resulted in the suppression of cancer cell proliferation in in vitro assays, and was particularly related to poor tumor differentiation, big tumor size, lymph node metastasis, and more advanced tumor stage. In the TCGA dataset, high KIF18A messenger RNA expression was associated with poor disease‐free and overall survival in patients with LUAD. In addition, multivariate analysis indicated that KIF18A is an independent prognostic factor of disease‐free and overall survival in LUAD.

          Conclusions

          Collectively, our results demonstrate that KIFl8A is highly expressed in LUAD. KIFl8A plays an important role in LUAD cell proliferation, but is a poor prognostic factor.

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          Most cited references 20

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          The kinesin-8 motor Kif18A suppresses kinetochore movements to control mitotic chromosome alignment.

          During vertebrate cell division, chromosomes oscillate with periods of smooth motion interrupted by abrupt reversals in direction. These oscillations must be spatially constrained in order to align and segregate chromosomes with high fidelity, but the molecular mechanism for this activity is uncertain. We report here that the human kinesin-8 Kif18A has a primary role in the control of chromosome oscillations. Kif18A accumulates as a gradient on kinetochore microtubules in a manner dependent on its motor activity. Quantitative analyses of kinetochore movements reveal that Kif18A reduces the amplitude of preanaphase oscillations and slows poleward movement during anaphase. Thus, the microtubule-depolymerizing kinesin Kif18A has the unexpected function of suppressing chromosome movements. Based on these findings, we propose a molecular model in which Kif18A regulates kinetochore microtubule dynamics to control mitotic chromosome positioning.
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            Activation of KIF4A as a prognostic biomarker and therapeutic target for lung cancer.

            To identify molecules that might be useful as diagnostic/prognostic biomarkers and as targets for the development of new molecular therapies, we screened genes that were highly transactivated in a large proportion of 101 lung cancers by means of a cDNA microarray representing 27,648 genes. We found a gene encoding KIF4A, a kinesin family member 4A, as one of such candidates. Tumor tissue microarray was applied to examine the expression of KIF4A protein and its clinicopathologic significance in archival non-small cell lung cancer (NSCLC) samples from 357 patients. A role of KIF4A in cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of KIF4A on mammalian cells was examined using Matrigel assays. Immunohistochemical staining detected positive KIF4A staining in 127 (36%) of 357 NSCLCs and 19 (66%) of 29 small-cell lung cancers examined. Positive immunostaining of KIF4A protein was associated with male gender (P = 0.0287), nonadenocarcinoma histology (P = 0.0097), and shorter survival for patients with NSCLC (P = 0.0005), and multivariate analysis confirmed its independent prognostic value (P = 0.0012). Treatment of lung cancer cells with small interfering RNAs for KIF4A suppressed growth of the cancer cells. Furthermore, we found that induction of exogenous expression of KIF4A conferred cellular invasive activity on mammalian cells. These data strongly implied that targeting the KIF4A molecule might hold a promise for the development of anticancer drugs and cancer vaccines as well as a prognostic biomarker in clinic.
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              Overexpression of kinesins mediates docetaxel resistance in breast cancer cells.

              Resistance to chemotherapy remains a major barrier to the successful treatment of cancer. To understand mechanisms underlying docetaxel resistance in breast cancer, we used an insertional mutagenesis strategy to identify proteins whose overexpression confers resistance. A strong promoter was inserted approximately randomly into the genomes of tumor-derived breast cancer cells, using a novel lentiviral vector. We isolated a docetaxel-resistant clone in which the level of the kinesin KIFC3 was elevated. When KIFC3 or the additional kinesins KIFC1, KIF1A, or KIF5A were overexpressed in the breast cancer cell lines MDA-MB231 and MDA-MB 468, the cells became more resistant to docetaxel. The binding of kinesins to microtubules opposes the stabilizing effect of docetaxel that prevents cytokinesis and leads to apoptosis. Our finding that kinesins can mediate docetaxel resistance might lead to novel therapeutic approaches in which kinesin inhibitors are paired with taxanes.
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                Author and article information

                Contributors
                zhongdsh@hotmail.com
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                25 March 2019
                May 2019
                : 10
                : 5 ( doiID: 10.1111/tca.2019.10.issue-5 )
                : 1103-1110
                Affiliations
                [ 1 ] Department of Oncology Tianjin Medical University General Hospital Tianjin China
                [ 2 ] Tianjin Lung Cancer Institute Tianjin Medical University General Hospital Tianjin China
                [ 3 ] Tianjin Medical University Graduate School Tianjin China
                Author notes
                [* ] Correspondence

                Diansheng Zhong, Department of Oncology, Tianjin Medical University General Hospital, No.154 Anshan Street, Heping District, Tianjin 300052, China.

                Tel: +86 22 6081 7007

                Fax: +86 22 8723 6114

                Email: zhongdsh@ 123456hotmail.com

                [†]

                These authors contributed equally.

                Article
                TCA13051
                10.1111/1759-7714.13051
                6500977
                30907518
                © 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 3, Tables: 3, Pages: 8, Words: 4483
                Product
                Funding
                Funded by: Natural Science Foundation of Tianjin
                Award ID: 16JCYBJC24400
                Funded by: National Natural Science Foundation of China
                Award ID: 31301160
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                tca13051
                May 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:06.05.2019

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