SNORA38B promotes proliferation, migration, invasion and epithelial-mesenchymal transition of gallbladder cancer cells via activating TGF-β/Smad2/3 signaling

Submitted: 25 October 2023
Accepted: 4 December 2023
Published: 28 December 2023
Abstract Views: 222
PDF: 65
HTML: 2
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

Evidence has shown that small nucleolar RNAs (snoRNAs) participate in the tumorigenesis in multiple cancers, including gallbladder cancer (GBC). Our results showed that SNORA38B level was increased in GBC tissues compared to adjacent normal tissues. Thus, this research aimed to explore the role and molecular mechanisms of SNORA38B in GBC. SNORA38B level between normal and GBC tissues was evaluated by RT-qPCR. Cell proliferation, apoptosis, migration, and invasion were tested by EdU assay, TUNEL staining and transwell assay, respectively on human intrahepatic biliary epithelial cells (HIBEpiCs) and the GBC cell lines, NOZ and GBC-SD. Expression of proteins in GBC cells was evaluated by immunofluorescence and Western blot assays. We found that, relative to normal tissues, SNORA38B level was notably elevated in GBC tissues. SNORA38B overexpression obviously enhanced GBC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), but weakened cell apoptosis. Conversely, SNORA38B downregulation strongly suppressed the proliferation and EMT of GBC cells and induced cell apoptosis and ferroptosis, whereas these phenomena were obviously reversed by TGF-β. Meanwhile, SNORA38B downregulation notably reduced the levels of phosphorylated-Smad2 and phosphorylated-Smad3 in GBC cells, whereas these levels were elevated by TGF-β. Collectively, downregulation of SNORA38B could inhibit GBC cell proliferation and EMT and induce ferroptosis via inactivating TGF-β1/Smad2/3 signaling. These findings showed that SNORA38B may be potential target for GBC treatment.

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

Citations

Song X, Hu Y, Li Y, Shao R, Liu F, Liu Y. Overview of current targeted therapy in gallbladder cancer. Signal Transduct Target Ther 2020;5:230. DOI: https://doi.org/10.1038/s41392-020-00324-2
Shen H, He M, Lin R, Zhan M, Xu S, Huang X, et al. PLEK2 promotes gallbladder cancer invasion and metastasis through EGFR/CCL2 pathway. J Exp Clin Cancer Res 2019;38:247. DOI: https://doi.org/10.1186/s13046-019-1250-8
Sung MK, Lee W, Lee JH, Song KB, Kim SC, Kwak BJ, et al. Comparing survival rate and appropriate surgery methods according to tumor location in T2 gallbladder cancer. Surg Oncol 2022;40:101693. DOI: https://doi.org/10.1016/j.suronc.2021.101693
Lee SE, Jang JY, Lim CS, Kang MJ, Kim SW. Systematic review on the surgical treatment for T1 gallbladder cancer. World J Gastroenterol 2011;17:174-80. DOI: https://doi.org/10.3748/wjg.v17.i2.174
Dutta U. Gallbladder cancer: can newer insights improve the outcome? J Gastroenterol Hepatol 2012;27:642-53. DOI: https://doi.org/10.1111/j.1440-1746.2011.07048.x
Tan CH, Lim KS. MRI of gallbladder cancer. Diagn Interv Radiol 2013;19:312-9. DOI: https://doi.org/10.5152/dir.2013.044
D'Hondt M, Lapointe R, Benamira Z, Pottel H, Plasse M, Letourneau R, et al. Carcinoma of the gallbladder: patterns of presentation, prognostic factors and survival rate. An 11-year single centre experience. Eur J Surg Oncol 2013;39:548-53. DOI: https://doi.org/10.1016/j.ejso.2013.02.010
Challakkara MF, Chhabra R. snoRNAs in hematopoiesis and blood malignancies: A comprehensive review. J Cell Physiol 2023;238:1207-25. DOI: https://doi.org/10.1002/jcp.31032
Huldani H, Gandla K, Asiri M, Romero-Parra RM, Alsalamy A, Hjazi A, et al. A comprehensive insight into the role of small nucleolar RNAs (snoRNAs) and SNHGs in human cancers. Pathol Res Pract 2023;249:154679. DOI: https://doi.org/10.1016/j.prp.2023.154679
Warner WA, Spencer DH, Trissal M, White BS, Helton N, Ley TJ, et al. Expression profiling of snoRNAs in normal hematopoiesis and AML. Blood Adv 2018;2:151-63. DOI: https://doi.org/10.1182/bloodadvances.2017006668
Williams GT, Farzaneh F. Are snoRNAs and snoRNA host genes new players in cancer? Nat Rev Cancer 2012;12:84-8. DOI: https://doi.org/10.1038/nrc3195
Yang X, Li Y, Li L, Liu J, Wu M, Ye M. SnoRNAs are involved in the progression of ulcerative colitis and colorectal cancer. Dig Liver Dis 2017;49:545-51. DOI: https://doi.org/10.1016/j.dld.2016.12.029
Zhang Z, Tao Y, Hua Q, Cai J, Ye X, Li H. SNORA71A promotes colorectal cancer cell proliferation, migration, and invasion. Biomed Res Int 2020;2020:8284576. DOI: https://doi.org/10.1155/2020/8284576
Zhang D, Zhou J, Gao J, Wu RY, Huang YL, Jin QW, et al. Targeting snoRNAs as an emerging method of therapeutic development for cancer. Am J Cancer Res 2019;9:1504-16.
Qin Y, Zhou Y, Ge A, Chang L, Shi H, Fu Y, et al. Overexpression of SNORA21 suppresses tumorgenesis of gallbladder cancer in vitro and in vivo. Biomed Pharmacother 2019;118:109266. DOI: https://doi.org/10.1016/j.biopha.2019.109266
Qin Y, Meng L, Fu Y, Quan Z, Ma M, Weng M, et al. SNORA74B gene silencing inhibits gallbladder cancer cells by inducing PHLPP and suppressing Akt/mTOR signaling. Oncotarget 2017;8:19980-96. DOI: https://doi.org/10.18632/oncotarget.15301
Zhuo Y LS, Hu W, Zhang Y, Shi Y, Zhang F, Zhang J, et al. Targeting SNORA38B attenuates tumorigenesis and sensitizes immune checkpoint blockade in non-small cell lung cancer by remodeling the tumor microenvironment via regulation of GAB2/AKT/mTOR signaling pathway. J Immunother Cancer 2022;10:e004113. DOI: https://doi.org/10.1136/jitc-2021-004113
Ma J, Li J, Wang Y, Chen W, Zheng P, Chen Y, et al. WSZG inhibits BMSC-induced EMT and bone metastasis in breast cancer by regulating TGF-β1/Smads signaling. Biomed Pharmacother 2020;121:109617. DOI: https://doi.org/10.1016/j.biopha.2019.109617
Yao Y, Zhou Z, Li L, Li J, Huang L, Li J, et al. Activation of Slit2/Robo1 Signaling promotes tumor metastasis in colorectal carcinoma through activation of the TGF-β/Smads pathway. Cells 2019;8:635. DOI: https://doi.org/10.3390/cells8060635
Colak S, Ten Dijke P. Targeting TGF-β signaling in cancer. Trends Cancer 2017;3:56-71. DOI: https://doi.org/10.1016/j.trecan.2016.11.008
Xu G, Yang F, Ding CL, Zhao LJ, Ren H, Zhao P, et al. Small nucleolar RNA 113-1 suppresses tumorigenesis in hepatocellular carcinoma. Mol Cancer 2014;13:216. DOI: https://doi.org/10.1186/1476-4598-13-216
Li JN WM, Chen YT, Kuo YL, Chen PS. Expression of SnoRNA U50A is associated with better prognosis and prolonged mitosis in breast cancer. Cancers (Basel) 2021;13:6304. DOI: https://doi.org/10.3390/cancers13246304
Cui C, Liu Y, Gerloff D, Rohde C, Pauli C, Köhn M, et al. NOP10 predicts lung cancer prognosis and its associated small nucleolar RNAs drive proliferation and migration. Oncogene 2021;40:909-21. DOI: https://doi.org/10.1038/s41388-020-01570-y
Liang J, Li G, Liao J, Huang Z, Wen J, Wang Y, et al. Non-coding small nucleolar RNA SNORD17 promotes the progression of hepatocellular carcinoma through a positive feedback loop upon p53 inactivation. Cell Death Differ 2022;29:988-1003. DOI: https://doi.org/10.1038/s41418-022-00929-w
Wu L, Zheng J, Chen P, Liu Q, Yuan Y. Small nucleolar RNA ACA11 promotes proliferation, migration and invasion in hepatocellular carcinoma by targeting the PI3K/AKT signaling pathway. Biomed Pharmacother 2017;90:705-12. DOI: https://doi.org/10.1016/j.biopha.2017.04.014
Wang Y, Zhao M, Zhao L, Geng Y, Li G, Chen L, et al. HBx-induced HSPA8 stimulates HBV replication and suppresses ferroptosis to support liver cancer progression. Cancer Res 2023;83:1048-61. DOI: https://doi.org/10.1158/0008-5472.CAN-22-3169
Wu Z, Lu Z, Li L, Ma M, Long F, Wu R, et al. Identification and validation of ferroptosis-related LncRNA signatures as a novel prognostic model for colon cancer. Front Immunol 2021;12:783362. DOI: https://doi.org/10.3389/fimmu.2021.783362
Chen P, Wu Q, Feng J, Yan L, Sun Y, Liu S, et al. Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis. Signal Transduct Target Ther 2020;5:51. DOI: https://doi.org/10.1038/s41392-020-0149-3
Chen HT, Liu H, Mao MJ, Tan Y, Mo XQ, Meng XJ, et al. Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy. Mol Cancer 2019;18:101. DOI: https://doi.org/10.1186/s12943-019-1030-2
Noh MG, Oh SJ, Ahn EJ, Kim YJ, Jung TY, Jung S, et al. Prognostic significance of E-cadherin and N-cadherin expression in gliomas. BMC Cancer 2017;17:583. DOI: https://doi.org/10.1186/s12885-017-3591-z
Sannino G, Marchetto A, Kirchner T, Grünewald TGP. Epithelial-to-mesenchymal and mesenchymal-to-epithelial transition in mesenchymal tumors: a paradox in sarcomas? Cancer Res 2017;77:4556-61. DOI: https://doi.org/10.1158/0008-5472.CAN-17-0032
Na TY, Schecterson L, Mendonsa AM, Gumbiner BM. The functional activity of E-cadherin controls tumor cell metastasis at multiple steps. Proc Natl Acad Sci USA 2020;117:5931-7. DOI: https://doi.org/10.1073/pnas.1918167117
Luo Y YT, Zhang Q, Fu Q, Hu Y, Xiang M, Peng H, et al. Upregulated N-cadherin expression is associated with poor prognosis in epithelial-derived solid tumours: A meta-analysis. Eur J Clin Invest 2018;48:e12903. DOI: https://doi.org/10.1111/eci.12903
Zhang M, Duan W, Sun W. LncRNA SNHG6 promotes the migration, invasion, and epithelial-mesenchymal transition of colorectal cancer cells by miR-26a/EZH2 axis. Onco Targets Ther 2019;12:3349-60. DOI: https://doi.org/10.2147/OTT.S197433
Zhao M, Mishra L, Deng CX. The role of TGF-β/SMAD4 signaling in cancer. Int J Biol Sci 2018;14:111-23. DOI: https://doi.org/10.7150/ijbs.23230
Lee JH, Massagué J. TGF-β in developmental and fibrogenic EMTs. Semin Cancer Biol 2022;86:136-45. DOI: https://doi.org/10.1016/j.semcancer.2022.09.004
Bertrand-Chapel A, Caligaris C, Fenouil T, Savary C, Aires S, Martel S, et al. SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4. Commun Biol 2022;5:1068. DOI: https://doi.org/10.1038/s42003-022-03994-6
Chen K, Cheng L, Qian W, Jiang Z, Sun L, Zhao Y, et al. Itraconazole inhibits invasion and migration of pancreatic cancer cells by suppressing TGF-β/SMAD2/3 signaling. Oncol Rep 2018;39:1573-82. DOI: https://doi.org/10.3892/or.2018.6281
Zhang Z, Zhu F, Xiao L, Wang M, Tian R, Shi C, et al. Side population cells in human gallbladder cancer cell line GBC-SD regulated by TGF-β-induced epithelial-mesenchymal transition. J Huazhong Univ Sci Technolog Med Sci 2011;31:749-55. DOI: https://doi.org/10.1007/s11596-011-0671-1
Liu ZY, Cao J, Zhang JT, Xu GL, Li XP, Wang FT, et al. Ring finger protein 125, as a potential highly aggressive and unfavorable prognostic biomarker, promotes the invasion and metastasis of human gallbladder cancers via activating the TGF- β1-SMAD3-ID1 signaling pathway. Oncotarget 2017;8:49897-914. DOI: https://doi.org/10.18632/oncotarget.18180
Sun L, Dong H, Zhang W, Wang N, Ni N, Bai X, et al. Lipid peroxidation, GSH depletion, and SLC7A11 Inhibition are common causes of EMT and ferroptosis in A549 Cells, but different in specific mechanisms. DNA Cell Biol 2021;40:172-83. DOI: https://doi.org/10.1089/dna.2020.5730
Huang P, Zhao H, Pan X, Li J, Pan W, Dai H, et al. SIRT3-mediated autophagy contributes to ferroptosis-induced anticancer by inducing the formation of BECN1-SLC7A11 complex. Biochem Pharmacol 2023;213:115592. DOI: https://doi.org/10.1016/j.bcp.2023.115592
Feng J, Li Y, He F, Zhang F. RBM15 silencing promotes ferroptosis by regulating the TGF-β/Smad2 pathway in lung cancer. Environ Toxicol 2023;38:950-61. DOI: https://doi.org/10.1002/tox.23741

Ethics Approval

all procedures were approved by the Ethics Committee of the Yancheng Third People's Hospital

Supporting Agencies

Jiangsu Provincial Commission of Health and Family Planning, Jiangsu Province “333 High-level Talents Cultivating Project"

How to Cite

Qin, Y., Li, J., Han, H., Zheng, Y., Lei, H., Zhou, Y., Wu, H., Zhang, G., Chen, X., & Chen, Z. (2023). SNORA38B promotes proliferation, migration, invasion and epithelial-mesenchymal transition of gallbladder cancer cells <em>via</em> activating TGF-β/Smad2/3 signaling . European Journal of Histochemistry, 67(4). https://doi.org/10.4081/ejh.2023.3899