Barrier to autointegration factor 1: A novel biomarker for gastric cancer

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1 ONCOLOGY LETTERS Brrier to utointegrtion fctor 1: A novel biomrker for gstric cncer JUNJUN LI 1, BINGBING HU 2, LEI FANG 3, YANG GAO 1, SHUAI SHI 3, HAOYU HE 1, XIAOMEI LIU 1 nd CAIJUN YUAN 1 1 Deprtment of Oncology, The First Affilited Hospitl of Jinzhou Medicl University, Jinzhou, Lioning ; 2 Deprtment of Infectious Diseses, The Third Affilited Hospitl of Xinxing Medicl University, Xinxing, Henn ; 3 Deprtment of Pthology nd Pthophysiology, Jinzhou Medicl University, Jinzhou, Lioning , P.R. Chin Received November 23, 2017; Accepted June 26, 2018 DOI: /ol Abstrct. Chin is country with high incidence of gstric cncer (GC), where the GC incidence nd the resultnt mortlity rtes ccount for 50% of those worldwide. Surgicl resection remins the primry tretment for GC. However, postopertive ptients hve poor prognosis s the mjority of ptients present with metstses t the time of dignosis. Therefore, the identifiction of novel tretment trgets is required. The present study imed to determine the effects of brrier to utointegrtion fctor 1 (BANF1) on the clinicl fetures nd prognosis of GC, which my id in discovering novel tumor dignostic biomrker nd tretment trget. The BANF1 gene expression profiles for norml nd gstric tumor tissues were downloded from the Gene Expression Omnibus GSE54129 dt set to nlyse the expression of BANF1 t the mrna levels. Then, online survivl nlysis ws performed using the GC dtbse with the Kpln Meier Plotter ( dt. To exmine the ssocition between BANF1 nd clinicl fetures nd prognosis, 132 postopertive GC pthologicl specimens were collected for immunohistochemicl nlyses. In the GSE54129 dt sets, BANF1 expression t the mrna level ws significntly higher in the tumor tissue compred with tht in the norml tissue. The sme result ws obtined in following the immunohistochemicl nlyses. In ddition, BANF1 expression ws ssocited with the ptient ge, tumor differentition nd infiltrtion depth. The survivl time of BANF1 high expression ptients ws shorter compred with tht of the low expression ptients, nd tumor differentition sttus nd tumor node metstsis Correspondence to: Professor Cijun Yun, Deprtment of Oncology, The First Affilited Hospitl of Jinzhou Medicl University, 2 The Fifth Section of Renmin Street, Jinzhou, Lioning , P.R. Chin E mil: @qq.com Key words: brrier to utointegrtion fctor 1, gstric cncer, biomrker, clinicl fetures, prognosis stge were independent prognostic fctors of the overll survivl of ptients with GC. The results of the present study suggest tht BANF1 is ssocited with the clinicl fetures nd prognosis of GC. It my be novel indictor of tumor prognosis nd potentil therpeutic trget for GC. Introduction Of the worldwide popultion of ptients with gstric cncer (GC), ~42% of the men nd 19% of the women re Chinese, nd the number of ptients suffering from GC hs incresed in recent yers (1,2). Although significnt progress hs been mde in the comprehensive tretment with surgery, the prognosis for postopertive ptients with GC remins poor (3). A detiled understnding of GC occurrence nd development, nd the fctors tht influence its prognosis re required. The brrier to utointegrtion fctor 1 (BANF1) fmily of proteins hs vriety of functions ssocited with the mintennce of the intct cellulr genome (4). BANF1 is n ~10 kd, highly conserved DNA binding protein tht forms homodimers. It ws first identified during the combintion of retrovirus nd host, promoting the fusion of retroviruses nd trget genes in vitro (5). As n importnt prt of the lmin, BANF1 hs essentil interctions with numerous cellulr proteins, including trnscription fctors nd DNA dmge repir proteins (6,7). It regultes gene expression, prticiptes in the formtion of kryotin structures nd is ssocited with cell mitosis (8). In recent yers, with the dvent of microrry technology, novel ides nd insights into the dignosis nd tretment of tumors hve been proposed (9). To understnd the effect of BANF1 on GC progression, its mrna nd protein expression levels in the gstric tumor tissue were compred with tht in djcent non tumorous tissue. BANF1 expression ws demonstrted to be upregulted in ptients with GC. In ddition, high expression of BANF1 ws identified s poor prognostic fctor. Furthermore, BANF1 expression correlted with ptient ge, tumor differentition nd infiltrtion depth. Therefore, BANF1 my be n oncogene. The results of the present study my id in developing reference in prognostic evlution of ptients with GC.

2 2 LI et l: BARRIER TO AUTOINTEGRATION FACTOR 1: A NOVEL BIOMARKER FOR GASTRIC CANCER Mterils nd methods Dt source. The microrry profiles of GC were extrcted from the Gene Expression Omnibus (GEO, nlm.nih.gov/geo/) dtbse under the ccession number of GSE A totl of 132 specimens, including 21 gene chips from djcent non tumorous tissue nd 111 gene chips from tissues of GC ptients, were vilble for the nlysis by GEO2R. The GEO dt ws pssed through qulity control nd homogeneous processing s previously described (9). A totl of 876 cses of gstric cncer used for prognostic nlysis were derived from the Kpln Meier Plotter dtbse. Survivl nlysis ws performed using the GC dtbse with the Kpln Meier (K M) estimtor dt. For comprison, the dt group (n=876) ws segmented into the high (n=604) nd low (n=272) BANF1 expression groups with the medin s the boundry. Clinicl GC specimen collection. Postopertive specimens were collected between June 2012 nd Jnury 2013 from The First Affilited Hospitl of Jinzhou Medicl University (Jinzhou, Chin), which included 23 norml nd 118 tumorous tissues. Specimens were plced in 10% neutrl buffered formlin for 24 h t room temperture (RT) nd then embedded in prffin wx block for storge. No ptients received ny other tretment prior to surgery. Tble I lists the clinicopthologicl fetures of ll ptients. The 8th edition tumor node metstsis (TNM) stging system of the Union for Interntionl Cncer Control ws the stndrd for tumor stging (10). The present study ws pproved by the Ethics Committees of the First Affilited Hospitl of Jinzhou Medicl University. Written informed consent ws obtined from ll ptients. Cell culture. The SGC 7901 nd MNK 45 GC cell lines (Hngzhou Bisi Biotechnology Co., Ltd., Hngzhou, Chin) were grown in RPMI 1640 (HyClone; GE Helthcre, Logn, UT, USA) supplemented with 10% fetl bovine serum (Gibco; Thermo Fisher Scientific, Inc., Wlthm, MA, USA), 100 U/ml penicillin nd 100 µg/ml streptomycin, t 37 C in 5% CO 2. Western blot nlysis. Cells were lysed in RIPA lysis buffer (ct. no. WLA016; Wnleibio Co., Ltd., Shenyng, Chin). Protein quntifiction ws performed using the Coomssie Brillint Blue method. Subsequently, 30 µg protein/lne were seprted by 12% SDS PAGE nd trnsferred to polyvinylidene fluoride membrne. The membrne ws blocked with 5% skim milk in Tris buffered sline with Tween 20 (TBST, 10 mm Tris HCl, 150 mm NCl, 0.1% Tween 20) for 1 h t RT, nd then incubted with the rbbit monoclonl nti BANF1 (ct. no. McAb129184; 1:500; Abcm, Cmbridge, UK) nd rbbit nti GAPDH (ct. no. WL01114; 1:2,000; Wnleibio Co., Ltd) ntibodies overnight t 4 C. The membrnes were wshed with TBST nd incubted with the got nti rbbit IgG secondry ntibody (ct. no. WLA023; 1:5,000; Wnleibio Co., Ltd. Shenyng, Chin). The bnds were visulized with LAS4010 imger (GE Helthcre Life Sciences, Little Chlfont, UK) using ECL Plus detection regent (Snt Cruz Biotechnology, Inc., Dlls, TX, USA). The densitometric quntifiction of protein bnds ws performed with GAPDH s control using ImgeJ softwre version (Ntionl Institutes of Helth, Bethesd, MD, USA). To vlidte the specificity of nti BANF1 ntibodies, rbbit nti BANF1 peptide specific ntibodies (ct. no. 4019P; 1:100; ProSci Inc., Powy, CA, USA) were used ginst the 15 mino cids ner the crboxy terminus of humn BANF1. After the diluted nti BANF1 ntibodies were preincubted with (+) nd without ( ) 0.5 mm nti BANF1 peptide specific ntibodies for 2 h t RT, they were used to determine BANF1 expression in SGC 7901 nd MNK 45 GC cells (11). The forementioned western blotting protocol ws performed in the sme wy following this incubtion. Immunohistochemistry. Tissue specimens were cut into successive 4 µm thick sections. Then, ntigen retrievl ws performed by heting the specimens using the pressure cooker ntigen repiring method t 120 C, followed by wshing with xylene nd grdul rehydrtion with descending ethnol series. Endogenous peroxidse ctivity in the specimens ws neutrlized vi incubtion with 3% hydrogen peroxide for 5 min t room temperture. Subsequently, the specimens were incubted in 5% bovine serum lbumin (ct. no. A8020; Beijing Solrbio Science & Technology Co., Ltd., Beijing, Chin) for 30 min t RT to block nonspecific binding. Then, the tissues were incubted with rbbit monoclonl nti BANF1 ntibody (1:100) overnight t 4 C. Following incubtion with the horserdish peroxidse conjugted got nti rbbit IgG secondry ntibodies (ct. no. WLA023; 1:500; Wnleibio Co., Ltd.) for 1 h t RT, ll sections were visulized using 3,3' diminobenzidine, nd the slides were counterstined with hemtoxylin (ct. no. WLA051; Wnleibio Co., Ltd.) for 1 min t RT (1,2). The coverslips were then mounted with nti fde mounting medium nd observed under microscope (mgnifiction x200; Olympus DP73; Jpn). Stining intensity score. The BANF1 expression intensity scores were determined by two independent observers blinded to the clinicopthologicl dt of ptients. In order to clculte the percentge of BANF1 positive cells, 100 cells were rndomly selected nd counted in five representtive fields of ech section. The positive expression re ws counted s follows: <5%, score of 0; <30%, score of 1; 30 70%, score of 2; nd >70%, score of 3. The stining intensity score ws grded s follows: Colourless, 0; wek, 1; intermedite, 2; nd strong, 3. The positive expression re nd stining intensity scores were multiplied (2). Sttisticl nlysis. All dt were nlysed with the SPSS 20.0 softwre progrm (IBM Corp., Armonk, NY, USA). Results were expressed s the men ± stndrd devition. Student's t tests were performed to evlute the differences in BANF1 mrna expression between the gstric tumor nd norml tissues. The Spermn's rnk correltion coefficient test ws used to nlyze the correltion between BANF1 expression nd clinicopthologicl fetures. The Mnn Whitney U test ws used to clculte the sttisticl significnce. Survivl curves were derived using the K M estimtor method nd compred using the log rnk test. Cox's proportionl hzrds model ws used to nlyze the effect of clinicopthologicl

3 ONCOLOGY LETTERS 3 Tble I. Assocition between BANF1 expression nd clinicopthologicl fetures. BANF1 expression Clinicopthologicl fetures No PR (%) P vlue Sex Mle Femle Age, yers < Tumor size, cm < Differentition Poor Moderte Well Infiltrtion depth T1/T T3/T Lymph node metstsis With Without Distnt metstsis M M TNM stging I nd II III nd IV P<0.05. PR, positive rte; BANF1, brrier to utointegrtion fctor 1; TNM, tumor node metstsis prmeters on ptient survivl. P<0.05 ws considered to indicte sttisticlly significnt difference. Results High expression of BANF1 mrna in GC tissues. In the GSE54129 dt sets, BANF1 expression in the gstric tumor tissues ws identified to be significntly higher compred with in the djcent non tumorous tissues (Fig. 1), s demonstrted by sttisticl prmeters for the BANF1 gene expression profiles in Tble II (P=1.50x10 87 ). Expression of BANF1 in GC cells. After the diluted nti BANF1 ntibodies were preincubted with the nti BANF1 peptide specific ntibodies, the ltter were used for western blotting. Exmintion of totl extrcts of SGC 7901 nd MNK 45 GC cells by immunoblotting reveled tht the ntibodies specificlly recognized 10 kd protein (Fig. 2, lnes 1 nd 2), which ws not present t the sme positions in the lnes with nti BANF1 peptide specific ntibody preincubtion (Fig. 2, lnes 3 nd 4). This indictes tht Figure 1. mrna expression of BANF1 in the GSE54129 dt sets. The gstric cncer microrry profiles were extrcted from the Gene Expression Omnibus dtbse under the ccession number of GSE BANF1 expression t the mrna level in tumor tissues ( ) ws significntly higher compred with tht in norml tissues ( ) (P=1.50x10 87 ). BANF1, brrier to utointegrtion fctor 1.

4 4 LI et l: BARRIER TO AUTOINTEGRATION FACTOR 1: A NOVEL BIOMARKER FOR GASTRIC CANCER Tble II. Sttisticl prmeters of BANF1 gene expression profiles. Gene nme ID Norml men Tumor men logfc t P vlue Adjust P vlue BANF _s_t x x10 83 P<0.05. BANF1, brrier to utointegrtion fctor 1; FC, fold chnge. BANF1 protein is expressed in SGC 7901 nd MNK 45 GC cells nd the nti BANF1 ntibody cn specificlly recognize the 10 kd BANF1 protein. Difference in BANF1 protein expression between the norml nd gstric tumor tissues. The intensity of BANF1 expression in the nucleus of GC cells vried (Fig. 3). The totl of 118 GC tissues included three cses of negtive BANF1 expression, eight wekly positive (+) smples, 42 modertely positive (++) smples nd 65 strongly positive (+++) smples. By contrst, negtive ( ) nd wekly positive (+) BANF1 stining ws detected in 18 smples nd five smples of 23 norml tissues, respectively, while no modertely positive or strongly positive stining ws detected. The protein expression of BANF1 in GC specimens ws significntly higher compred with tht in norml tissues (P<0.001; Tble III). Tble III. BANF1 expression in gstric cncer. BANF1 expression Group No PR (%) P vlue Norml <0.001 Cncer P<0.05. PR, positive rte; BANF1, brrier to utointegrtion fctor 1. BANF1 expression is ssocited with ptient ge, nd the degree of GC differentition nd depth of invsion. The immunohistochemistry results re summrized in Tble I. The rtes of positive BANF1 expression in GC tissues with low, medium nd high differentition sttuses were 100, 98 nd 71.4%, respectively. The BANF1 expression in poorly differentited GC tissues ws significntly higher compred with tht in modertely nd highly differentited tissues, nd ws ssocited with the differentition degree of tumors (P<0.001). In ddition, BANF1 expression correlted with the ptient ge (P=0.001) nd tumor infiltrtion depth (P=0.011). Effect of BANF1 expression on the overll survivl (OS) of postopertive ptients. Online survivl nlysis ws performed using the GC dtbse in K M Plotter, which reveled tht the survivl times for ptients with high BANF1 mrna expression ws significntly reduced compred with tht for the low expression ptients [log rnk test, P<0.001; hzrd rtio (HR), 2.37; 95% confidence intervl (CI), ; Fig. 4A]. Subsequently, the K M estimtor method ws used to nlyze the effect of BANF1 expression on the postopertive overll survivl (OS) time of ptients, the follow up period ws 150 months, nd the mortlity ws considered s the end point during the follow up period. The survivl curve suggested tht the OS of the ptients with low BANF1 expression ws significntly incresed compred with the OS of high expression ptients (log rnk test, P<0.001; Fig. 4B). Thus, the level of BANF1 expression my be used s prognostic indicte for ptients with GC. Next, the ge, the TNM stge nd other clinicl fetures were incorported into the Cox regression model. It ws reveled tht the tumor differentition sttus nd the TNM stge were independent fctors ffecting the OS of ptients with GC (Tble IV). Figure 2. Detection of BANF1 protein in SGC 7901 nd MNK 45 gstric cncer cells by western blot nlysis. Lnes 1, 3, 5 nd 7 correspond to totl cell extrcts of SGC 7901 gstric cncer cells. Lnes 2, 4, 6 nd 8 correspond to totl cell extrcts of MNK 45 gstric cncer cells. The diluted nti BANF1 ntibodies were preincubted with (+) nd without ( ) 0.5 mm nti BANF1 peptide specific ntibodies. The positions of the BANF1 proteins re mrked t 10 kd in lnes 1 nd 2, which were not present t the sme position in lnes 3 nd 4. BANF1, brrier to utointegrtion fctor 1. Discussion The five yer survivl rtes of postopertive ptients with GC vry between 15 nd 60%, with GC dignosis nd detection lcking effective biomrkers (1,12). Despite the significnt dvnces in the understnding of GC pthogenesis, there is no effective therpy vilble for GC tretment. Therefore, the identifiction of effective biomrkers is required to significntly improve the erly dignosis rte nd prognosis for ptients with GC.

5 ONCOLOGY LETTERS 5 Figure 3. Immunohistochemistry stining of BANF1 in gstric cncer. (A) Norml gstric tissues. (B) Atypicl hyperplsi tissues. (C) Gstrointestinl stroml tumor tissues. (D) Poorly differentited denocrcinom. (E) Modertely differentited denocrcinom. (F) Highly differentited denocrcinom. (A) No BANF1 expression ( ); (F) wekly stined; (E) modertely positive expression (++) (C) nd (D) strongly positive expression (+++) Mgnifiction, x200. BANF1, brrier to utointegrtion fctor 1. Figure 4. Survivl curve for ptients with GC ptients. (A) The K M curve of BANF1 mrna expression from the K M Plotter dt (log rnk test, P<1x10 16 ). (B) The K M curve of BANF1 protein expression (log rnk test, P<0.001). The overll survivl of the ptients in the low expression group ws significntly improved compred with tht of the ptients in the high expression group. BANF1, brrier to utointegrtion fctor 1; Cum, cumultive; K M, Kpln Meier. BANF1 encodes highly conserved BAF protein consisting of 89 mino cids nd binding to double strnded DNA with high ffinity. It ws discovered due to its involvement in the integrtion of retrovirl DNA (13). Regultion of BAF phosphoryltion, medited by cell or virus, regultes numerous cellulr ctivities, including protein dimeriztion, its binding to DNA, nd subcellulr locliztion of the protein (14 16). Additionlly, BAF prticiptes in kryomitosis, kryon ssembly, kryoplsm regultion nd the DNA dmge response (17). As the first protein tht is recruited to the core re of kryolemm, the role of BAF in mitosis is importnt. Once BAF is locted t the core of chromtin, other kryothec nchoring nd membrne spnning proteins re recruited to complete the nucler membrne reformtion, which is key step in cell mitosis (18,19). Previous studies hve demonstrted tht the bsence of BAF or the blockge of its phosphoryltion results in bnorml morphologicl bnormlities of the cryothec (13). This cuses berrnt nucler rchitecture nd disrupts norml cell mitosis process (20). Abnorml mitosis my cuse chromosoml instbility, which is considered chrcteristic chnge in mlignnt tumor cells (21). BAF is ble to positively or negtively regulte cell ctivities, lthough the specific mechnisms remin uncler. At the erly stges of Cenorhbditis elegns embryogenesis, BAF regultes sem cell fusion by suppressing the expression of epithelil fusion filure 1 fused protein nd the development of germ cells (22). It hs been reported tht BAF inhibits trnscription in vccini virus deficiency in the virl B1 kinse (23,24). Activtion of BANF1 my inhibit skin inflmmtion in psoritic lesions by inctivtion of S100A9 nd c Jun, but it my lso promote kertinocyte prolifertion (5). A coding muttion of the BANF1 lnine 12 to threonine ws reported to be ssocited with BANF1 protein instbility nd bnormlities of the cryothec, which hs been confirmed s the hereditry fundmentl of Néstor Guillermo Progeri syndrome (NGPS) (25). The disruption of the interction between Prelmin A nd BAF my be the cuse of NGPS (26). In ddition, certin studies hve reported tht BANF1

6 6 LI et l: BARRIER TO AUTOINTEGRATION FACTOR 1: A NOVEL BIOMARKER FOR GASTRIC CANCER Tble IV. Cox multivrite regression nlysis of the ssocition between the clinicl fctors nd overll survivl. Clinicopthologicl fctors Reltive risk (95% CI) P vlue BANF ( ) Negtive ( ) Positive (+) Age, yers ( ) <60 Sex ( ) Mle Femle Tumor size, cm ( ) <5 Differentition Poor Moderte ( ) Poor ( ) Well Infiltrtion depth ( ) T1/T2 T3/T4 Lymph node metstsis ( ) With Without TNM stging ( ) <0.001 Phse I nd II Phse III nd IV P<0.05. CI, confidence intervl; BANF1, brrier to utointegrtion fctor 1; TNM, tumor node metstsis. expression is incresed in brest nd oesophgel cncer, nd is ssocited with the poor prognosis of ptients (27,28). Furthermore, its role is essentil in regulting the S phse process, stem cell self renewl, nd differentition nd prolifertion of kertinocytes (5,29). Trgeted therpy nd individulized tumor tretment re directed ginst specific gene muttions nd proteins. Bsed on the notion of tumor therpy tretment, it is essentil to identify suitble oncogenes to develop smll molecules or monoclonl ntibodies to control the disese. BANF1 hs been demonstrted to be trget for the tretment of tumors with specilized inhibitor imed t BAF phosphoryltion medited by vccini relted kinse 1, which blocks cell cycle progression in tumor cells by interfering with the cryomitotic phse (30). In the present study, the expression level of BANF1 ws demonstrted to be significntly incresed in GC tissues, nd ws inversely correlted with the ptient ge, tumor differentition sttus nd infiltrtion depth. Furthermore, the survivl curve nlysis reveled tht the prognosis for ptients with high BANF1 expression ws poor t the mrna nd protein levels. To further investigte the ssocition between the clinicl chrcteristics nd prognosis, Cox regression nlysis ws performed. The results suggested tht tumor differentition sttus nd TNM stge were independent risk fctors ffecting the OS of ptients with GC. The HR of BANF1 ws (95% CI, ; P=0.362) in the Cox regression nlysis, but BANF1 significntly impcts poor survivl of GC in the K M nlysis (log rnk P<0.001). This indictes tht BANF1 hs n impct on prognosis together with other fctors, but is not n independent prognostic fctor by itself. A limittion of the present study ws tht the BANF1 protein levels in the tissues from ptients with GC were only detected by immunohistochemistry, nd tht western blot nlysis is required to support the immunohistochemistry results. In summry, BANF1 expression ws upregulted in clinicl GC tissues, nd ws ssocited with the tumor ge, infiltrtion depth nd differentition. Additionlly, the results of the present study confirmed tht BANF1 closely correltes with dverse outcomes in GC ptients undergoing surgery. Tken together, the present study is the first to propose tht high BANF1 expression my be used s novel indictor of poor prognosis or s therpeutic trget for ptients with GC. Acknowledgements Not pplicble. Funding The present study ws supported by the Lioning Province Science nd Technology Project (grnt no ). Avilbility of dt nd mterils The dtsets generted nd/or nlyzed during the present study re vilble in the GEO repository ( gov/geo/) nd the Kpln Meier Plotter dtbse ( com/nlysis/index.php?p=service&cncer=gstric). Authors' contributions JL, BH, LF, YG, SS nd HH performed the experiments nd nlyzed the dt. JL, LF, XL nd CY designed the study nd co wrote the mnuscript. JL, YG, LF nd HH were involved in revising the mnuscript. All the uthors hve red nd pproved the finl version of the mnuscript. Ethics pprovl nd consent to prticipte The present study ws pproved by the Ethics Committees of the First Affilited Hospitl of Jinzhou Medicl University. Written informed consent ws obtined from ll ptients. Ptient consent for publiction Written informed consent ws obtined from ll ptients regrding the publiction of the dt nd ssocited imges.

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