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KIF23 Enhances Cell Proliferation in Pancreatic Ductal Adenocarcinoma and Is a Potent Therapeutic Target

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KIF23 Enhances Cell Proliferation in Pancreatic Ductal Adenocarcinoma and Is a Potent Therapeutic Target 1394 Original Article Page 1 of 15 KIF23 enhances cell proliferation in pancreatic ductal adenocarcinoma and is a potent therapeutic target Chun-Tao Gao1#, Jin Ren2#, Jie Yu1,3#, Sheng-Nan Li1, Xiao-Fan Guo1, Yi-Zhang Zhou1 1Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China; 2Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China; 3The First Hospital of Shanxi Medical University, Taiyuan, China Contributions: (I) Conception and design: CT Gao, J Ren; (II) Administrative support: CT Gao; (III) Provision of study materials or patients: J Yu; (IV) Collection and assembly of data: J Ren, SN Li, YZ Zhou; (V) Data analysis and interpretation: XF Guo, J Ren; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Chun-Tao Gao. Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Huan-hu-xi Road, He-xi District, Tianjin 300060, China. Email: [email protected]. Background: In recent research, high expression of kinesin family member 23 (KIF23), one of the kinesin motor proteins involved in the regulation of cytokinesis, has been shown to be related to poor prognosis in glioma and paclitaxel-resistant gastric cancer, as a results of the enhancement of proliferation, migration, and invasion. In this study, we analyzed the role of KIF23 in the progression of pancreatic ductal adenocarcinoma. Methods: A bioinformatic method was used to analyze the KIF23 mRNA level in pancreatic tumor tissues compared with normal pancreatic tissues and to analyze the connection between high KIF23 expression and prognosis. We examined the expression of KIF23 using immunohistochemistry and analyzed the connection between the expression of KIF23 and clinicopathological features in pancreatic ductal adenocarcinoma patients. In addition, a colony formation assay, MTT assay, and western blot assay were performed in vitro, along with a mouse xenograft model in vivo, to analyze the effect of KIF23 on proliferation. Further, the correlation between KIF23 and CDCA8 was analyzed by TCGA and immunohistochemical data. Results: Bioinformatic results showed that KIF23 mRNA expression was higher in pancreatic tumor tissues than in normal pancreatic tissues and a poor prognosis has been linked to the high expression of KIF23. Immunohistochemistry revealed that KIF23 was highly expressed at the protein level and high expression of KIF23 correlated with adverse clinicopathological features. Our experimental results demonstrated that knockdown of KIF23 could inhibit the proliferation of pancreatic cells. Further, a positive correlation between KIF23 and CDCA8 expression existed, and KIF23 might promote pancreatic cancer proliferation by affecting CDCA8 expression. Conclusions: Our data showed that high expression of KIF23 is associated with a poor prognosis, and KIF23 might be a potential therapeutic target for pancreatic ductal adenocarcinoma. Keywords: Kinesin family member 23 (KIF23); proliferation; pancreatic cancer; prognosis; therapeutic target Submitted Feb 26, 2020. Accepted for publication Aug 27, 2020. doi: 10.21037/atm-20-1970 View this article at: http://dx.doi.org/10.21037/atm-20-1970 © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2020;8(21):1394 | http://dx.doi.org/10.21037/atm-20-1970 Page 2 of 15 Gao et al. KIF23 promotes pancreatic ductal adenocarcinoma proliferation Introduction We present the following article in accordance with the ARRIVE reporting checklist (available at http://dx.doi. In recent years, significant progress has been made in terms org/10.21037/atm-20-1970). of cancer research and treatment. However, there has not been any remarkable advance in survival rates for pancreatic cancer (1,2). The morbidity and mortality of pancreatic Methods ductal adenocarcinoma (PDAC) have risen significantly Bioinformatic analysis in recent years: with 56,770 new cases (male 29,940 and female 26,830 cases) of pancreatic cancer and 45,750 deaths We used GEPIA (http://gepia.cancer-pku.cn/) (16) to (male 23,800 and female 21,950 cases) expected in 2019 (3), collate and analyze The Cancer Genome Atlas (TCGA) 55,400 new cases (male 29,200 and female 26,240 cases) data with a threshold of P<0.05 and LogFC >1 or <−1 for and 44,330 deaths (male 23,020 and female 21,310 cases) the differential genes, and we divided the patients into two reported in 2018 (4), and 53,670 new cases (male 27,970 groups using the median value as the basis for Kaplan-Meier and female 25,700 cases) and 43,090 (male 22,300 and survival analysis. The 95% confidence interval is marked female 20,790 cases) deaths in 2017 (5). The five-year with a dotted line. In addition, the correlation between survival rate for pancreatic cancer is very low, and it is KIF23 and CDCA8 was analyzed by GEPIA. considered one of the worst malignant tumors due to its high surgical mortality rate and low cure rate (6). In China, Sample collection the mortality rate from pancreatic cancer is almost equal to the incidence rate because of the poor prognosis (7). Based on the institutional review board's approval, all of the Although there are treatment options for pancreatic cancer, 82 adult PDAC patients with PDAC included in this study such as chemotherapy and radiotherapy, surgical resection is were from Tianjin Medical University Cancer Institute and still the main treatment of choice. However, most patients Hospital from 2009 to 2017. These cases were included on with pancreatic cancer are diagnosed at an advanced stage the basis of a clear pathological diagnosis. The informed and surgery is feasible in less than 20% of cases (8). Recent consent of each patient was obtained. All procedures studies have found that the occurrence of pancreatic performed in research involving human participants cancer is largely affected by gender, aging, smoking, and complied with the ethical standards of the institution and/or diabetes (9). However, the pathogenesis of pancreatic the National Research Council and with the 1964 Helsinki cancer is complex and our understanding remains limited. Declaration and its subsequent amendments or similar Therefore, more in-depth studies on the mechanism of ethical standards. pancreatic cancer may help us to identify novel therapeutic targets (10). Immunohistochemistry Kinesin family member 23 (KIF23), a human homolog of mouse KIF23, is one of the kinesin motor proteins The expression of KIF23 was detected in paraffin- involved in the regulation of cytokinesis (11,12). Based on embedded tumor tissue by a rabbit-anti-KIF23 antibody cDNA microarray or by quantitative reverse transcription- (ab235955, 1:200 dilution; Abcam, USA), following the polymerase chain reaction (PCR), KIF23 overexpression procedure specified in the immunohistochemistry kit has been detected in lung cancer, breast cancer, gliomas, (ZSGB-BIO, pv6000, China). Briefly, we fixed tumor paclitaxel-resistant gastric cancer, hepatocellular carcinoma, tissues and matched normal adjacent tissues in 10% neutral- and pancreatic cancer (13,14), and has been associated with buffered formalin and embedded them in paraffin blocks poor prognosis for several cancers (15). by the pathology department of our hospital. Then, the In our research, we discovered that high expression paraffin sections (4 μm) were placed into a microwave oven of KIF23 was associated with poor prognosis by for 15 minutes to repair the antigens and were then cooled immunohistochemical analysis of tumor sections and at room temperature. Endogenous peroxidase was blocked, clinical data from patients with PDAC. We also found that and sections were incubated with an anti-KIF23 antibody knockdown of KIF23 decreased proliferation in PANC- overnight at 4 , followed by a goat anti-rabbit secondary 1 and BxPC-3 PDAC cells, and suppression of KIF23 antibody at 37 for 1 hour. Sections were stained with ℃ in PANC-1 cells inhibited tumor growth in nude mice. 3,3-diaminobenzidin (DAB) at room temperature for ℃ © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2020;8(21):1394 | http://dx.doi.org/10.21037/atm-20-1970 Annals of Translational Medicine, Vol 8, No 21 November 2020 Page 3 of 15 10 minutes and images were then recorded by microscopy then incubated with a primary antibody at 4 overnight. (Olympus BX43). All samples were evaluated by two After a further three washes, PVDF was incubated with a ℃ independent pathologists. secondary antibody for 1 hour at room temperature and To analyze the results, KIF23 nuclear staining was scored then washed again. Finally, the ECL substrate reagent kit using the 4-point scale (0, no staining; 1+, light staining (GE Healthcare, RPN 2109, USA) was used to visualize at high magnification; 2+, intermediate staining; and 3+, the protein bands on the imaging capture system (Alpha dark staining of the linear membrane at low magnification). Innovation). According to the distribution of scores of KIF23 staining intensity, samples were divided into high expression (2+ to Cell culture 3+) and low expression (0 to 1+) groups. The PDAC cells of PANC-1 and BxPC-3 were cultured in 1640 medium (Gibco,
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