Abstract
Since the incidence and mortality of colorectal cancer (CRC) are increasing in recent years, the research on the pathogenesis of colorectal cancer has attracted more and more attention. Here, our results confirmed that the mRNA expression level and proteins accumulation of TUFT1 were significantly increased in CRC tissues from late-stage CRC patients (III + IV) (p < 0.001), indicated by qPCR and IHC assay. The TUFT1 expression was positively correlated with tumor stage by analyzing 126 specimens from CRC patients. Next, we found that up-regulation of TUFT1 enhanced the migration and invasion of LoVo cells, whereas the down-regulation of TUFT1 observably weakened the migration and invasion of SW837 cells, indicating that TUFT1 promotes the metastasis of CRC cells. In addition, TUFT1 overexpression increased the number of mammary spheres and vincristine resistance of LoVo cells by sphere formation assay and measuring the IC50 value, suggesting the TUFT1 promotes stemness and the vincristine resistance of CRC cells. Finally, we found that TUFT1 overexpression increased p-AKT in LoVo cells, while down-regulation of TUFT1 decreased the p-AKT levels in SW837 cells. Therefore, we determined that the function of TUFT1 in CRC depends on PI3K/AKT pathway. Taken together, these data demonstrated that TUFI1 facilitates metastasis, stemness, and vincristine resistance of colorectal cancer cells via activation of PI3K/AKT pathway, which might act as a promising therapeutic target for CRC.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
All data generated or analyzed during this study are included in this published article.
References
Bahrami A et al (2018) Therapeutic potential of targeting PI3K/AKT pathway in treatment of colorectal cancer: rational and progress. J Cell Biochem 119:2460–2469. https://doi.org/10.1002/jcb.25950
Bashir MM, Abrams WR, Tucker T, Sellinger B, Budarf M, Emanuel B, Rosenbloom J (1998) Molecular cloning and characterization of the bovine and human tuftelin genes. Connect Tissue Res 39(1–3):13–24. https://doi.org/10.3109/03008209809023908
Brody H (2015) Colorectal cancer. Nature 521:S1. https://doi.org/10.1038/521S1a
Cao W, Wei W, Zhan Z, **e D, **e Y, **ao Q (2018) Regulation of drug resistance and metastasis of gastric cancer cells via the microRNA647-ANK2 axis. Int J Mol Med 41:1958–1966. https://doi.org/10.3892/ijmm.2018.3381
Chao MW, Lai MJ, Liou JP, Chang YL, Wang JC, Pan SL, Teng CM (2015) The synergic effect of vincristine and vorinostat in leukemia in vitro and in vivo. J Hematol Oncol 8:82. https://doi.org/10.1186/s13045-015-0176-7
Chen H, Zhou L, Wu X, Li R, Wen J, Sha J, Wen X (2016) The PI3K/AKT pathway in the pathogenesis of prostate cancer. Front Biosci 21:1084–1091. https://doi.org/10.2741/4443
Cheng C, **e Z, Li Y, Wang J, Qin C, Zhang Y (2018) PTBP1 knockdown overcomes the resistance to vincristine and oxaliplatin in drug-resistant colon cancer cells through regulation of glycolysis. Biomed Pharmacother 108:194–200. https://doi.org/10.1016/j.biopha.2018.09.031
Colakoglu T et al (2008) Clinicopathological significance of PTEN loss and the phosphoinositide 3-kinase/Akt pathway in sporadic colorectal neoplasms: is PTEN loss predictor of local recurrence? Am J Surg 195:719–725. https://doi.org/10.1016/j.amjsurg.2007.05.061
Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB (2019) Colorectal cancer. Lancet 394:1467–1480. https://doi.org/10.1016/s0140-6736(19)32319-0
Deutsch D et al (2002) The human tuftelin gene and the expression of tuftelin in mineralizing and nonmineralizing tissues. Connect Tissue Res 43:425–434. https://doi.org/10.1080/03008200290001186
Dou C et al (2019) Hypoxia-induced TUFT1 promotes the growth and metastasis of hepatocellular carcinoma by activating the Ca(2+)/PI3K/AKT pathway. Oncogene 38:1239–1255. https://doi.org/10.1038/s41388-018-0505-8
Faes S, Dormond O (2015) PI3K and AKT: unfaithful partners in cancer. Int J Mol Sci 16:21138–21152. https://doi.org/10.3390/ijms160921138
Frommann K, Appl B, Hundsdoerfer P, Reinshagen K, Eschenburg G (2018) Vincristine resistance in relapsed neuroblastoma can be efficiently overcome by Smac mimetic LCL161 treatment. J Pediatr Surg 53:2059–2064. https://doi.org/10.1016/j.jpedsurg.2018.01.012
Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT (2017) The PI3K pathway in human disease. Cell 170:605–635. https://doi.org/10.1016/j.cell.2017.07.029
Gennery BA (1985) Vincristine neurotoxicity. Lancet 2:385. https://doi.org/10.1016/s0140-6736(85)92516-4
Guo X, Li Q, Wang YF, Wang TY, Chen SJ, Tian ZW (2018) Reduced lipocalin 2 expression contributes to vincristine resistance in human colon cancer cells. Recent Pat Anticancer Drug Discov 13:248–254. https://doi.org/10.2174/1574892813666171221120504
Hamzehzadeh L, Atkin SL, Majeed M, Butler AE, Sahebkar A (2018) The versatile role of curcumin in cancer prevention and treatment: a focus on PI3K/AKT pathway. J Cell Physiol 233:6530–6537. https://doi.org/10.1002/jcp.26620
Hu JC, Zhang CH, Yang Y, Kärrman-Mårdh C, Forsman-Semb K, Simmer JP (2001) Cloning and characterization of the mouse and human enamelin genes. J Dent Res 80:898–902. https://doi.org/10.1177/00220345010800031001
Huxley RR, Ansary-Moghaddam A, Clifton P, Czernichow S, Parr CL, Woodward M (2009) The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence. Int J Cancer 125:171–180. https://doi.org/10.1002/ijc.24343
Janku F, Yap TA, Meric-Bernstam F (2018) Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol 15:273–291. https://doi.org/10.1038/nrclinonc.2018.28
Latiff ZA, Kamal NA, Jahendran J, Alias H, Goh BS, Syed Zakaria SZ, Jamal R (2010) Vincristine-induced vocal cord palsy: case report and review of the literature. J Pediatr Hematol Oncol 32:407–410. https://doi.org/10.1097/MPH.0b013e3181e01584
Lien EC, Dibble CC, Toker A (2017) PI3K signaling in cancer: beyond AKT. Curr Opin Cell Biol 45:62–71. https://doi.org/10.1016/j.ceb.2017.02.007
Liu W et al (2019) TUFT1 promotes triple negative breast cancer metastasis, stemness, and chemoresistance by up-regulating the Rac1/β-catenin pathway. Front Oncol 9:617. https://doi.org/10.3389/fonc.2019.00617
Liu W et al (2017) TUFT1 is expressed in breast cancer and involved in cancer cell proliferation and survival. Oncotarget 8:74962–74974. https://doi.org/10.18632/oncotarget.20472
Luo X et al (2019) Exosomal lncRNA HNF1A-AS1 affects cisplatin resistance in cervical cancer cells through regulating microRNA-34b/TUFT1 axis. Cancer Cell Int 19:323. https://doi.org/10.1186/s12935-019-1042-4
Ma C, Nie ZK, Guo HM, Kong Y (2020) MiR-671–5p plays a promising role in restraining osteosarcoma cell characteristics through targeting TUFT1. J Biochem Mol Toxicol 34(7):e22490. https://doi.org/10.1002/jbt.22490
Manning BD, Toker A (2017) AKT/PKB signaling: navigating the network. Cell 169:381–405. https://doi.org/10.1016/j.cell.2017.04.001
Mao Z et al (2001) The human tuftelin gene: cloning and characterization. Gene 279:181–196. https://doi.org/10.1016/s0378-1119(01)00749-1
Minaříková M, Oralová V, Veselá B, Radlanski RJ, Matalová E (2015) Osteogenic profile of mesenchymal cell populations contributing to alveolar bone formation. Cell Tissue Organs 200:339–348. https://doi.org/10.1159/000439165
Neuss N, Neuss MN (1990) Chapter 6 therapeutic use of bisindole alkaloids from catharanthus. In: Brossi A, Suffness M (eds) The alkaloids: chemistry and pharmacology, vol 37. Academic Press, Cambridge, pp 229–240. https://doi.org/10.1016/S0099-9598(08)60097-8
Ollikainen M, Gylling A, Puputti M, Nupponen NN, Abdel-Rahman WM, Butzow R, Peltomäki P (2007) Patterns of PIK3CA alterations in familial colorectal and endometrial carcinoma. Int J Cancer 121:915–920. https://doi.org/10.1002/ijc.22768
Paniello RC, Bhatt NK, Chernock R (2018) Toxicity trial of canine posterior cricoarytenoid intramuscular vincristine injections. Laryngoscope 128:E247-e250. https://doi.org/10.1002/lary.26998
Patel SG, Ahnen DJ (2018) Colorectal cancer in the young. Curr Gastroenterol Rep 20:15. https://doi.org/10.1007/s11894-018-0618-9
Potter JD (1999) Colorectal cancer: molecules and populations. J Natl Cancer Inst 91:916–932. https://doi.org/10.1093/jnci/91.11.916
Said R, Tsimberidou AM (2014) Pharmacokinetic evaluation of vincristine for the treatment of lymphoid malignancies. Expert Opin Drug Metab Toxicol 10:483–494. https://doi.org/10.1517/17425255.2014.885016
Shilo D et al (2019) Tuftelin is required for NGF-induced differentiation of PC12 Cells. J Mol Neurosci 68:135–143. https://doi.org/10.1007/s12031-019-01292-1
Slattery ML (2000) Diet, lifestyle, and colon cancer. Semin Gastrointest Dis 11:142–146
Song M, Bode AM, Dong Z, Lee MH (2019) AKT as a therapeutic target for cancer. Res 79:1019–1031. https://doi.org/10.1158/0008-5472.Can-18-2738
Taghizadehghalehjoughi A, Sezen S, Hacimuftuoglu A, Güllüce M (2019) Vincristine combination with Ca(+2) channel blocker increase antitumor effects. Mol Biol Rep 46:2523–2528. https://doi.org/10.1007/s11033-019-04706-w
Tenesa A, Dunlop MG (2009) New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet 10:353–358. https://doi.org/10.1038/nrg2574
Van der Jeught K, Xu HC, Li YJ, Lu XB, Ji G (2018) Drug resistance and new therapies in colorectal cancer. World J Gastroenterol 24:3834–3848. https://doi.org/10.3748/wjg.v24.i34.3834
Vasan N, Baselga J, Hyman DM (2019) A view on drug resistance in cancer. Nature 575:299–309. https://doi.org/10.1038/s41586-019-1730-1
Wrobel P, Ahmed S (2019) Current status of immunotherapy in metastatic colorectal cancer. Int J Colorectal Dis 34:13–25. https://doi.org/10.1007/s00384-018-3202-8
Wu G, Zhou H, Li D, Zhi Y, Liu Y, Li J, Wang F (2020) LncRNA DANCR upregulation induced by TUFT1 promotes malignant progression in triple negative breast cancer via miR-874–3p-SOX2 axis. Exp Cell Res 396:112331. https://doi.org/10.1016/j.yexcr.2020.112331
**ao Z et al (2020) Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis. Int J Biol Sci 16:2296–2305. https://doi.org/10.7150/ijbs.45457
Yu X et al (2018) Osteopontin promotes hepatocellular carcinoma progression via the PI3K/AKT/Twist signaling pathway. Oncol Lett 16:5299–5308. https://doi.org/10.3892/ol.2018.9281
Zangooei MH, Jalili S (2013) Protein fold recognition with a two-layer method based on SVM-SA, WP-NN and C4.5 (TLM-SNC). Int J Data Min Bioinform 8:203–223
Zhou B et al (2016) TUFT1 regulates metastasis of pancreatic cancer through HIF1-snail pathway induced epithelial-mesenchymal transition. Cancer Lett 382:11–20. https://doi.org/10.1016/j.canlet.2016.08.017
Zhu J, Tan Z, Hollis-Hansen K, Zhang Y, Yu C, Li Y (2017) Epidemiological trends in colorectal cancer in china: an ecological study. Dig Dis Sci 62:235–243. https://doi.org/10.1007/s10620-016-4362-4
Author information
Authors and Affiliations
Contributions
YY, TZ, and LW designed the study, supervised the data collection, analyzed the data, interpreted the data, prepared the manuscript for publication, and reviewed the draft of the manuscript. All the authors have read and approved the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors state that there are no conflicts of interest to disclose.
Ethical Approval
The protocol was approved by the Ethics Committee of Ankang Central Hospital.
Informed Consent
Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Yang, Y., Zhang, T. & Wu, L. TUFT1 Facilitates Metastasis, Stemness, and Vincristine Resistance in Colorectal Cancer via Activation of PI3K/AKT Pathway. Biochem Genet 59, 1018–1032 (2021). https://doi.org/10.1007/s10528-021-10051-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10528-021-10051-0