HOXB7 Promotes Proliferation and Metastasis of Glioma by Regulating the Wnt/Β-Catenin Pathway

European Review for Medical and Pharmacological Sciences 2019; 23: 2476-2485 HOXB7 promotes proliferation and metastasis of glioma by regulating the Wnt/β-catenin pathway

X.-Y. HUO1, X.-Y. ZHANG2, F. YUAN3, X.-Y. ZHAO4, B.-A. YOU1

1Heart Centre, Qilu Hospital of Shandong University (Qingdao), Qingdao, China 2Laboratory Medicine, Qingdao Oncology Hospital, Qingdao, China 3Department of Geriatric Neurology, Qilu Hospital of Shandong University (Qingdao), Qingdao, China 4Medical Examination Center, Qilu Hospital of Shandong University (Qingdao), Qingdao, China

Abstract. – OBJECTIVE: The purpose of this ulating the Wnt/β-catenin signaling pathway, and study was to investigate the expression level of is conspicuously associated with lymph node or HOXB7 in gliomas and its effect on the prolifer- distant metastasis and poor prognosis. ation and metastasis of gliomas, as well as its regulatory mechanism of promoting the malig- Key Words: nant progression of glioma. HOXB7, Wnt/β-catenin signaling pathway, Glioma, PATIENTS AND METHODS: In this study, 32 Metastasis, Proliferation. pairs of glioma tumor tissue specimens and adjacent ones were collected and the HOXB7 expression levels in these tissues were detected using quantitative Real Time Polymerase Chain Introduction Reaction (qRT-PCR), and the interplay between HOXB7 level and clinical parameters of glioma was analyzed. QRT-PCR was used to further ver- Glioma is the most common primary malignant ify the expression of HOXB7 in glioma cell lines. central nervous system tumor in adults, with pre- 1-3 The sh-HOXB7 knockdown model was con- valence of 40%-50% in all intracranial tumors . structed in glioma cell lines, and the influence Although the current treatment methods (surgery, of HOXB7 on the biological function of glioma radiotherapy, chemotherapy) are constantly im- cells was examined by Cell Counting Kit-8 (CCK- proving, the efficacy has not been conspicuously 8) and transwell assay. Meanwhile, Western blot improved4,5. However, the risk factors for its in- was applied to explore whether HOXB7 can promote the progression of glioma through the Wnt/ cidence have been studied intensively, including β-catenin pathway. genetics, diet, unhealthy lifestyle and precance- RESULTS: QRT-PCR results showed that the rous lesions. More than half of clinical glioma pa- level of HOXB7 in glioma tumor tissue speci- tients have undergone radical surgery; however, mens was conspicuously higher than that in the micrometastasis has emerged as a direct cause of adjacent normal ones. The occurrence of lymph postoperative metastasis and recurrence of glio- node or distant metastasis was higher and the 6,7 prognosis was worse in patients with higher mas . The pathogenesis of glioma has not been HOXB7 expression. In addition, compared with fully elucidated, so the difficulties in its diagnosis the sh-NC group, cell proliferation, invasiveness and treatment are one of the important reasons for and migration ability of the sh-HOXB7 group its high morbidity and mortality7,8. Therefore, elu- decreased conspicuously. Subsequently, the cidation of the molecular mechanism, prediction, Western blot result revealed that the expression diagnosis and prognosis of glioma metastasis and of key proteins in the Wnt/β-catenin signaling proliferation are important aspects of colorectal pathway was conspicuously reduced in the sh- 9 HOXB7 group, thereby promoting the malignant cancer research . progression of glioma. The Wnt/β-catenin signaling pathway is a hi- CONCLUSIONS: HOXB7 may promote the in- ghly conserved signal transduction pathway in vasivenessRETRACTED and migration of glioma cells via reg- the evolution of organisms, regulating and con- 2476 Corresponding Author: Beian You, MD; email: [email protected] HOXB7 promotes glioma trolling many life processes10. In the process of Cell Lines and Reagents embryonic development, it does not only deter- The human glioma cell lines (U251, U87, mine the growth and differentiation of cells, but T98-G, A172) and HEB, the human brain nor- also regulates the differentiation and formation mal glial cell, were purchased from the Ameri- of important organs such as cardiovascular and can Type Culture Collection (ATCC; Manassas, central nervous cells. In vivo, the Wnt/β-catenin VA, USA). High glucose Dulbecco’s Modified pathway directly controls tumor cell prolifera- Eagle Medium (DMEM) medium and fetal bo- tion, differentiation, polarization, apoptosis and vine serum (FBS) were purchased from Life anti-apoptosis11. The dysregulation of this pa- Technologies (Gaithersburg, MD, USA). Cells thway has been confirmed to be closely related were cultured in high glucose DMEM medium to a variety of tumors, such as cervical cancer, containing 10% FBS at a 37°C incubator with 12,13 breast cancer, melanoma, glioma, etc . The 5% CO2. abnormality in this pathway can cause an accu- mulation of intracellular β-catenin, which can Transfection Assay enter the nucleus and regulate downstream gene Negative control (sh-NC) and siRNA contai- expression, thereby promoting tumorigenesis14,15. ning HOXB7 interference sequence (sh-HOXB7) HOXB7 belongs to the homeobox gene HOX were purchased from Shanghai Jima Company family. The homeobox gene was first discovered (Shanghai, China). The cells were seeded in a in Drosophila and is a type of gene that plays a 6-well plate and grown to a cell density of 70%; pivotal role in the embryonic development and then siRNA transfection was conducted using cell differentiation of animals including humans. Lipofectamine 2000 (Invitrogen, Carlsbad, CA, Evidence suggests that disorders in HOX gene USA). After that, the cells were collected 48 h la- expression may induce the occurrence of lots of ter for quantitative Real Time-Polymerase Chain tumors15,16. It is known to be abnormally expressed Reaction (qRT-PCR) analysis and function expe- in tumors such as pancreatic and colorectal cancer, riments. and is associated with tumor grading and diffe- rentiation17-19. In recent years, researchers16,17 have Cell Proliferation Assay analyzed the role of HOXB7 in tumors and found The proliferation of the three cell lines was that HOXB7 is involved in tumor cell proliferation examined using the Cell Counting Kit-8 (CCK-8; and invasiveness, and its expression is closely asso- Dojindo, Kumamoto, Japan). The main steps were ciated with clinicopathological features. as follows: first, 100 μL of cell suspension was ad- Therefore, this study separately illustrated the ded (containing 2000 cells) in each well, then 10 possible role of HOXB7 in the progression of μL of CCK-8 solution was added and the incuba- glioma through the activation of the Wnt/β-caten- tion continued for 1 h in the cell culture incubator. in pathway and explored its molecular regulation After that, a microplate reader was used to analy- mechanism to bring new ideas for the diagnosis ze cell proliferation at 450 nm. Wells containing and treatment of glioma. the corresponding amount of cell culture medium and CCK-8 solution but no cells were considered as a blank control. Patients and Methods Transwell Assay Patients and Glioma Samples Cells were seeded in a 6-well plate when Tumor and paracancerous tissues from 32 pa- the density reached to 3 × 105/well. Liposo- tients who underwent glioma radical resection mal transfection experiment was performed were collected. None of the patients received any when cell fusion reached 80%. Positive clones radiotherapy or chemotherapy before surgery. were selected for expanded culture for sub- The pathological classification and staging cri- sequent transwell experiment. The specific teria of glioma were performed according to the steps were as follows: first, the Matrigel and International Union against cash-NCer (UICC) the serum-free medium were diluted as 1:100, glioma staging criteria. Patients and their fami- and the dilution was used to soak the transwell lies in this study have been fully informed and chamber. 100-mesh diluted Matrigel was ad- signed informed consent. This study was appro- ded in the chamber, and the whole device was ved by the Ethics Committee of Qilu Hospital of placed on a clean bench and sterilized by ultra- ShandongRETRACTED University. violet ray overnight before proceeding to the 2477 X.-Y. Huo, X.-Y. Zhang, F. Yuan, X.-Y. Zhao, B.-A. You next experiment. Subsequently, 200 μL was 100°C for 5 min, and an appropriate amount of added to the upper chamber, and 600 mL of the loading buffer was applied. After being se- serum-free medium was added to the lower parated through sodium dodecyl sulphate (SDS) chamber to balance the pressure. After the in- gel electrophoresis, the protein was transferred vading chamber was taken out, the cells on the to polyvinylidene difluoride (PVDF; Millipore, membrane were fixed with absolute ethanol Billerica, MA, USA) via wet transfer method, and stained with crystal violet staining. Tumor and 5% skim milk was used to block the pro- cells that did not invade the stroma were gently tein for 1 hour. After that, the corresponding wiped off with a cotton swab, and those had primary antibodies were added and incubated successfully invaded the Matrigel were retai- in the refrigerator at 4°C overnight. After being ned and counted under a high-power microsco- washed with Tris-Buffered Saline and Tween pe (x 200). The number of invading cells in 10 (TBST; Sigma-Aldrich, St. Louis, MO, USA) high power fields was counted, and the count 3 times the next day, the corresponding secon- was repeated three times. dary antibodies (1:1000) were added, and after 2 hours of incubation at room temperature, the Quantitative Real Time-Polymerase Chain protein was developed with enhanced chemi- Reaction (qRT-PCR) luminescence (ECL; Thermo Fisher Scientific, Real Time-quantitative Polymerase Chain Re- Waltham, MA, USA). action (RT-qPCR) was performed to analyze the mRNA levels of HOXB7, β-catenin and β-actin in Statistical Analysis glioma tissues and cells. Total RNA was extracted Statistical analysis was performed using Stati- in one step using the TRIzol reagent (Invitrogen, stical Product and Service Solutions (SPSS) 22.0 Carlsbad, CA, USA) and reverse transcribed into statistical software (IBM, Armonk, NY, USA). the first strand of complementary deoxyribose nu- The t-test was used to compare the measurement cleic acid (cDNA) using Primescript RT Reagent data, and the categorical variables were analyzed (TaKaRa, Otsu, Shiga, Japan) reverse transcrip- using χ2-test or Fisher’s exact probability method. tion kit, and primers were designed by Primer 5.0 Survival analysis was performed using the software. The qRT-PCR reaction was performed Kaplan-Meier method and survival curves were using SYBR® Premix Ex TaqTM (TaKaRa, Otsu, plotted. Data were expressed as mean ± standard Shiga, Japan) and StepOne Plus Real Time-PCR deviation (x–±s), and p-values < 0.05 were conside- System. The following primers were designed for red statistically significant. qRT-PCR reaction: HOXB7: F: 5’-ATCTACCC- CTGGATGCGAAGCT-3’, R: 5’-GCGTCAG- GTAGCGATTGTAGTG-3’; β-catenin: F: Results 5’-AACGTCTTCTCCCTTCTCTC-3’, R: 5’- CCA- CAGCAGCAGAAACT-3’; β-actin:F: 5’-AAG- HOXB7 Had a High Level in Glioma GTGAAGGTCGGAGTCAA-3’, R: 5’-AATGA- Tissues and Cell Lines AGGGGTCATTGATGG-3’. Each sample was HOXB7 level was conspicuously elevated in subjected to a three-hole repeated experiment and glioma tissues compared to paracancerous tis- repeated twice. The Bio-Rad PCR instrument was sues, and the difference was statistically signi- used to analyze and process the data (Bio-Rad, ficant (Figure 1A). In addition, compared with Hercules, CA, USA). The β-actin and U6 genes HEB, HOXB7 was conspicuously expressed in were used as internal parameters, and the gene glioma cell lines, especially in U251 and U87 expression was calculated by the 2-ΔΔCt method. cells, so we chose these two cells for subsequent experiments (Figure 1B). Western Blot The tissue or cells to be analyzed were col- HOXB7 Expression was Correlated lected. The lysate pre-cooled on the ice was ad- with Lymph Node and Distant Metastasis ded in the cell or tissue samples, shaken, mixed in Glioma vigorously and then placed on the ice for clea- According to 32 pairs of glioma tumor tis- vage for 30 min. The protein concentration was sues and paracancerous tissues, the relationship determined by the bicinchoninic acid (BCA) between HOXB7 expression and age, sex, patho- method (Pierce, Waltham, MA, USA). The pro- logical stage, lymph node metastasis and distant tein sampleRETRACTED was denatured in a water bath at metastasis of glioma patients was analyzed. As 2478 HOXB7 promotes glioma

Figure 1. HOXB7 is highly expressed in glioma tissues and cell lines. A, qRT-PCR was used to detect the HOXB7 expression in glioma tumor tissues and adjacent tissues. B, qRT-PCR was used to detect HOXB7 expression levels in glioma cell lines. C, qRT-PCR was used to detect differential expression of HOXB7 in glioma tumor tissues with or without lymph node metastasis. D, qRT-PCR was used to detect differential expression of HOXB7 in glioma tumor tissues with or without distant metastasis. E, The overall survival curve of the Kaplan-Meier in patients with glioma was shown based on the HOXB7 expression. F, The progression-free survival curve of the Kaplan-Meier was analyzed in patients with glioma based on HOXB7 expression and the prognosis of patients with high expression was significantly worse than that of the low expression group. Data are mean ± SD, *p<0.05, **p<0.01, ***p<0.001. RETRACTED 2479 X.-Y. Huo, X.-Y. Zhang, F. Yuan, X.-Y. Zhao, B.-A. You shown in Table I, low expression of HOXB7 was Knockdown of EHMT2 Changed the positively correlated with glioma lymph node Activation of the Wnt/β-Catenin Pathway metastasis and distant metastasis, but not with To further explore how HOXB7 promotes the age, gender and pathological stage (Figure 1C malignant progression of glioma, we examined and 1D). In addition, to explore the interplay the key proteins in the Wnt/β-catenin pathway between the expression of HOXB7 and the pro- and found by Western blot that the expression of gnosis of patients with glioma, we collected rele- β-catenin, CTNNB1, SOX4, CCND1, CCND2, vant follow-up data. The Kaplan-Meier survival C-MYC decreased conspicuously after knock- curves showed that low expression of HOXB7 down of HOXB7 (Figure 3A). was conspicuously associated with overall survival rate and disease-free survival time (p<0.05; β-Catenin was Lowly Expressed in Figure 1E and 1F). Glioma Tissues and Cell Lines Subsequently, we found through bioinformati- Knockdown of HOXB7 Inhibited Cell cs research that HOXB7 and β-catenin may have Proliferation, Migration and Invasiveness some relationship in glioma. The expression le- To explore the impact of HOXB7 on the fun- vel of β-catenin was found markedly increased in ction of glioma cells, we first successfully con- glioma tumor tissue specimens compared to the structed the sh-HOXB7 expression model and adjacent ones (Figure 3B). In addition, β-catenin verified it by qRT-PCR (Figure 2A). We then per- was conspicuously higher in glioma cell lines than formed cell proliferation, invasion and migration HEB, and the difference was statistically signifi- experiments in the U251 and U87 cell lines, re- cant (Figure 3C). Therefore, we examined HOXB7 spectively. It was found that the proliferation of and β-catenin levels in 32 glioma tumor tissues and cells in the sh-HOXB7 group was conspicuously in cell lines by qRT-PCR, and found that these two decreased according to the CCK-8 assay, and the showed a positive correlation (Figure 3D). difference was statistically significant (Figure 2B). In addition, we used the transwell assay to HOXB7 Modulated β-Catenin Expression explore the role of HOXB7 in the migration and in Human Glioma Cells invasiveness of glioma cells. The results showed To figure out the interplay between HOXB7 that the number of transmembrane glioma cells and β-catenin, we constructed and transfected a in the transwell chamber of the sh-HOXB7 group β-catenin knockdown vector into a tumor cell line was conspicuously smaller than that of the NC based on sh-HOXB7 transfection and qRT-PCR group, suggesting that sh-HOXB7 inhibited the was performed to verify the expression efficiency cell invasive ability (Figure 2C). (Figure 4A). Subsequently, the β-catenin protein

Table I. Association of HOXB7 expression with clinicopathologic characteristics of glioma.

HOXB7 expression

Parameters Number of cases Low (%) High (%) p-value

Age (years) 0.716 <60 14 8 6 ≥60 12 6 6 Gender 0.716 Male 12 6 6 Female 14 8 6 T stage 0.793 T1-T2 18 10 8 T3-T4 8 4 4 Lymph node metastasis 0.014 No 19 13 6 Yes 7 1 6 Distance metastasis 0.005 No 18 13 5 YesRETRACTED 8 1 7 2480 HOXB7 promotes glioma

Figure 2. Silencing HOXB7 inhibits glioma cell proliferation as well as invasion and migration. A, qRT-PCR verified the interference efficiency of HOXB7 after transfection of sh-HOXB7 in U251 and U87 cell lines. B, The CCK-8 assay revealed that the proliferation of cells in the sh-HOXB7 group was conspicuously decreased. C, The transwell migration invasion assay detected that sh-HOXB7 inhibited the invasion and migration ability of glioma cells in U251 and U87 cell lines (Magnifica- tion: 40 ×). Data are mean ± SD, *p<0.05.

expression was examined by Western blotting (Fi- grade is progressively worse3. Molecular genetics gure 4B). The proliferation and migration were de- and epigenetics have always been the research hot- tected by CCK-8 and transwell migration assays. spots of tumors. The establishment of new disci- The results showed that the invasiveness and mi- plines such as tumor molecular epidemiology and gration ability of the sh-HOXB7 and the sh-β-cat- molecular pathology has further revealed the inci- enin group was lower than that of the sh-HOXB7 dence, development, proliferation and invasiveness and the sh-NC group (Figure 4C). of central nervous system tumors. The molecular mechanism of neovascularization also opens the prelude to molecularly targeted therapy for glio- Discussion ma4-7. Among them, molecular targeted therapy is developing from the initial single target inhibition Glioma is the most common primary intracra- to multi-target therapy, and the interaction betwe- nial tumor, with multiple invasive growth and un- en multi-target cell signaling pathways and bypass clear borders. Tumor cells usually grow in brain tis- activation has become a research hotspot in the sue withinRETRACTED 2 cm of the tumor, and the pathological field of targeted therapy7,8. 2481 X.-Y. Huo, X.-Y. Zhang, F. Yuan, X.-Y. Zhao, B.-A. You

The HOXB7 gene is a class of evolutionarily tect the expression of HOXB7 in 32 glioma tis- highly conserved DNA sequences with a con- sues and its adjacent paracancerous tissues, and served sequence of 183 nucleotides in length found that HOXB7 expression in tumor tissues encoding a homeodomain (HD) consisting of 61 was conspicuously higher than that in the adja- amino acids16,17. The region is folded into three cent tissues and was positively correlated with helical structures containing an amino-terminal lymph node and distant metastasis. Therefore, we arm and passed through the helix between the believe that HOXB7 may play a role in promoting second and third helices. The turn-helix mo- glioma. Tumor metastasis is the process in which dule binds specifically to the DNA sequence of tumor cells are scattered from the in situ to the the target gene, and recognizes a 10-12 bp DNA distal target organ and adapt to the new tissue sequence centered at 5’-TAAI, -3’17. In this stu- microenvironment. To further explore the effect dy, we focused on the effects of HOXB7 on the of HOXB7 on the biological function of glioma, biological function of glioma cells. The results we constructed a sh-HOXB7 model using lenti- showed that HOXB7 was conspicuously up-re- virus. The results of the CCK-8 and invasion and gulated in gliomas, suggesting that HOXB7 has migration assays indicated that HOXB7 can pro- a potential cancer-promoting effect in gliomas. mote the proliferation and metastasis of glioma To further figure out the role of HOXB7 in the and plays a pivotal role in glioma, but its specific progression of glioma, we used RT-PCR to de- molecular mechanism remains elusive.

Figure 3. Silencing HOXB7 downregulates the expression of the Wnt/β-catenin signaling pathway in gliomas. A, Western blot verified the expression levels of β-catenin, CTNNB1, SOX4, CCND1, CCND2, C-MYC after transfection of sh-HOXB7 in U251 and U87 cell lines. B, qRT-PCR detected differential expression of β-catenin in glioma tumor tissues and adjacent tissues. C, qRT-PCR detected β-catenin expression in glioma cell lines. D, The expression of HOXB7 was significantly positively correlatedRETRACTED with β-catenin in glioma tissues. Data are mean ± SD, *p<0.05, **p<0.01, ***p<0.001. 2482 HOXB7 promotes glioma

Figure 4. HOXB7 regulates the expression of β-catenin in glioma tissues and cell lines. A, qRT-PCR was used to detect HOXB7 expression levels in cell lines co-transfected with HOXB7 and β-catenin. B, Western blot was used to detect β-catenin expression level in cell lines co-transfected with HOXB7 and β-catenin. C, The transwell migration assay was used to analyze the role of HOXB7 and β-catenin in the regulation of invasion and migration of glioma cells (Magnification: 40×). Data are mean ± SD, *#p<0.05.

The Wnt signaling pathway includes at least vel of free β-catenin in the cytoplasm is extremely three pathways, one canonical pathway, the Wn- low, and does not enter the nucleus to regulate the t/β- catenin pathway, and two non-canonical pa- expression of the corresponding genes10-12. The thways9. There is no Wnt signal in normal matu- Wnt signal inhibits the activity of Gsk-3p binding re cells. Most of the β-catenin in the cytoplasm to Axin by transmitting a signal to the intracel- binds to E-cadherin on the cell membrane, and a lular scattered protein Dsh (disheveled Dsh/Dvl) small part binds to APC, Gsk-3p and Axin in the by binding to the specific membrane receptor cytoplasm. After the complex forms, Gsk-36 can Fz, so that β-catenin cannot be phosphorylated degradeRETRACTED β-catenin by phosphorylation, so the le- and degraded and accumulates in the cytoplasm 2483 X.-Y. Huo, X.-Y. Zhang, F. Yuan, X.-Y. Zhao, B.-A. You and enters the nucleus. In the nucleus, β-catenin References binds to T cell transcription factor TCF/NGer factor LEF, and activates Cyclin D1 and C-myc 1) Hadjipanayis CG, Stummer W. 5-ALA and FDA ap- gene expression to promote cell proliferation13-15. proval for glioma surgery. J Neurooncol 2019; 141: The uncertainty of the Wnt activation pathway 479-486. and the specificity of its receptor protein incre- 2) Ma Q, Long W, Xing C, Chu J, Luo M, Wang HY, Liu Q, Wang RF ase the difficulty of studying the Wnt signaling . Cancer stem cells and immuno- 15 suppressive microenvironment in glioma. Front pathways . Abnormalities in the Wnt/β-catenin Immunol 2018; 9: 2924. signaling pathway are closely related to the de- uan iu ang i 12,13 3) Y X, L D, W Y, L X. Significance of nucle- velopment of multiple tumors . 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Therefore, we Pharmacol 2018; 9: 1503. focused on the role of HOXB7 in activating the 6) Ameratunga M, Pavlakis N, Wheeler H, Grant R, Si- Wnt/β-catenin pathway to promote the develop- mes J, Khasraw M. Anti-angiogenic therapy for high-grade glioma. Cochrane Database Syst Rev ment of glioma. To demonstrate whether HOXB7 2018; 11: CD008218. promotes the development of glioma by regula- Bready D, Placantonakis DG ting the Wnt/β-catenin pathway, we examined 7) . Molecular pathogenesis of low-grade glioma. Neurosurg Clin N Am the expression changes of key proteins including 2019; 30: 17-25. β-catenin, CTNNB1, SOX4, CCND1, CCND2, 8) Mao F, Wang B, Xiao Q, Cheng F, Lei T, Guo D. LRIG and C-MYC after knockdown of HOXB7 by We- proteins in glioma: functional roles, molecular me- stern blot. The result suggested that HOXB7 can chanisms, and potential clinical implications. 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Int J Biochem Cell Biol 2016; 77: 23-29. that HOXB7 may promote the malignant progres- Ma S, Lei Y, Zhang L, Wang J. sion of glioma by regulating β-catenin. 12) Research on the inhibiting effect of tanshinone IIA on colon cancer cell growth via COX-2-Wnt/beta-catenin signaling pathway. J BUON 2018; 23: 1337-1342. Conclusions 13) Hu XY, Hou PF, Li TT, Quan HY, Li ML, Lin T, Liu JJ, Bai J, Zheng JN. The roles of Wnt/beta-catenin We found that HOXB7 was greatly associated signaling pathway related lncRNAs in cancer. Int with lymph node metastasis and distant metasta- J Biol Sci 2018; 14: 2003-2011. sis and poor prognosis. In addition, it may inhibit 14) Cheng X, Xu X, Chen D, Zhao F, Wang W. Thera- the invasion and migration of glioma by regula- peutic potential of targeting the Wnt/beta-catenin ting the Wnt/β-catenin signaling pathway. signaling pathway in colorectal cancer. Biomed Pharmacother 2019; 110: 473-481. 15) Fan X, Huang X, Li Z, Ma X. MicroRNA-372-3p pro- Conflict of Interest motes the epithelial-mesenchymal transition in breast carcinoma by activating the Wnt pathway. The AuthorsRETRACTED declare that they have no conflict of interest. J BUON 2018; 23: 1309-1315. 2484 HOXB7 promotes glioma

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