Trefoil factor 3 promotes pancreatic carcinoma progression via WNT pathway activation mediated by enhanced WNT ligand expression.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
25 03 2022
25 03 2022
Historique:
received:
24
10
2021
accepted:
01
03
2022
revised:
10
02
2022
entrez:
25
3
2022
pubmed:
26
3
2022
medline:
13
4
2022
Statut:
epublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality with a dismal prognosis that has changed little over the past few decades. Further understanding of the molecular pathology of PDAC progression is urgently required in order to improve the prognosis of patients with PDAC. Herein, it was observed that trefoil factor 3 (TFF3) expression was elevated in PDAC, and was positively correlated with a worse overall patient survival outcome. Forced expression of TFF3 promoted oncogenic functions of PDAC cells in vitro including cell proliferation, survival, foci formation, cancer stem cell-like behavior and invasion, ex vivo colony growth in 3D-Matrigel, and xenograft growth in vivo. Depletion or pharmacological inhibition of TFF3 inhibited these same processes. RNA-Seq analysis and subsequent mechanistic analyses demonstrated that TFF3 increased the expression of various WNT ligands to mediate WNT pathway activation required for TFF3-stimulated PDAC progression. Combined pharmacological inhibition of TFF3 and WNT signaling significantly attenuated PDAC xenograft growth and potentiated the therapeutic efficacy of gemcitabine in both ex vivo and in vivo models. Hence, a mechanistic basis for combined inhibition of pathways enhancing PDAC progression is provided and suggests that inhibition of TFF3 may assist to ameliorate outcomes in PDAC.
Identifiants
pubmed: 35332126
doi: 10.1038/s41419-022-04700-4
pii: 10.1038/s41419-022-04700-4
pmc: PMC8948291
doi:
Substances chimiques
Ligands
0
TFF3 protein, human
0
Trefoil Factor-3
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
265Informations de copyright
© 2022. The Author(s).
Références
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
pubmed: 29313949
doi: 10.3322/caac.21442
Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, et al. Pancreatic cancer. Nat Rev Dis Prim. 2016;2:16022.
pubmed: 27158978
doi: 10.1038/nrdp.2016.22
Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J, et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015;6:6744.
pubmed: 25855536
doi: 10.1038/ncomms7744
Pandey V, Zhang M, You M, Zhang W, Chen R, Zhang W, et al. Expression of two non-mutated genetic elements is sufficient to stimulate oncogenic transformation of human mammary epithelial cells. Cell Death Dis. 2018;9:1147.
pubmed: 30451834
pmcid: 6242831
doi: 10.1038/s41419-018-1177-6
Perry JK, Kannan N, Grandison PM, Mitchell MD, Lobie PE. Are trefoil factors oncogenic? Trends Endocrinol Metab. 2008;19:74–81.
pubmed: 18054496
doi: 10.1016/j.tem.2007.10.003
Dieckow J, Brandt W, Hattermann K, Schob S, Schulze U, Mentlein R, et al. CXCR4 and CXCR7 mediate TFF3-induced cell migration independently from the ERK1/2 signaling pathway. Invest Ophthalmol Vis Sci. 2016;57:56–65.
pubmed: 26780310
doi: 10.1167/iovs.15-18129
Belle NM, Ji Y, Herbine K, Wei Y, Park J, Zullo K, et al. TFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths. Nat Commun. 2019;10:4408.
pubmed: 31562318
pmcid: 6764942
doi: 10.1038/s41467-019-12315-1
Cui HY, Wang SJ, Song F, Cheng X, Nan G, Zhao Y, et al. CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression. Signal Transduct Target Ther. 2021;6:268.
pubmed: 34262017
pmcid: 8280106
doi: 10.1038/s41392-021-00677-2
Perera O, Evans A, Pertziger M, MacDonald C, Chen H, Liu DX, et al. Trefoil factor 3 (TFF3) enhances the oncogenic characteristics of prostate carcinoma cells and reduces sensitivity to ionising radiation. Cancer Lett. 2015;361:104–11.
pubmed: 25748388
doi: 10.1016/j.canlet.2015.02.051
Chen RM, Chiou YS, Chong QY, Poh HM, Tan TZ, Zhang MY, et al. Pharmacological inhibition of TFF3 enhances sensitivity of CMS4 colorectal carcinoma to 5-fluorouracil through Inhibition of p44/42 MAPK. Int J Mol Sci. 2019;20:6215.
pmcid: 6940926
doi: 10.3390/ijms20246215
Yusufu A, Shayimu P, Tuerdi R, Fang C, Wang F, Wang H. TFF3 and TFF1 expression levels are elevated in colorectal cancer and promote the malignant behavior of colon cancer by activating the EMT process. Int J Oncol. 2019;55:789–804.
pubmed: 31432157
pmcid: 6741840
Yusup A, Huji B, Fang C, Wang F, Dadihan T, Wang HJ, et al. Expression of trefoil factors and TWIST1 in colorectal cancer and their correlation with metastatic potential and prognosis. World J Gastroenterol. 2017;23:110–20.
pubmed: 28104986
pmcid: 5221274
doi: 10.3748/wjg.v23.i1.110
Pandey V, Zhang M, Chong QY, You M, Raquib AR, Pandey AK, et al. Hypomethylation associated enhanced transcription of trefoil factor-3 mediates tamoxifen-stimulated oncogenicity of ER
pubmed: 29100386
pmcid: 5652779
doi: 10.18632/oncotarget.20461
Taniguchi Y, Kurokawa Y, Takahashi T, Mikami J, Miyazaki Y, Tanaka K, et al. Prognostic value of Trefoil factor 3 expression in patients with gastric cancer. World J Surg. 2018;42:3997–4004.
pubmed: 30039286
doi: 10.1007/s00268-018-4737-0
Kirikoshi H, Katoh M. Expression of TFF1, TFF2 and TFF3 in gastric cancer. Int J Oncol. 2002;21:655–9.
pubmed: 12168114
You ML, Chen YJ, Chong QY, Wu MM, Pandey V, Chen RM, et al. Trefoil factor 3 mediation of oncogenicity and chemoresistance in hepatocellular carcinoma is AKT-BCL-2 dependent. Oncotarget 2017;8:39323–44.
pubmed: 28445151
pmcid: 5503616
doi: 10.18632/oncotarget.16950
Okada H, Kimura MT, Tan D, Fujiwara K, Igarashi J, Makuuchi M, et al. Frequent trefoil factor 3 (TFF3) overexpression and promoter hypomethylation in mouse and human hepatocellular carcinomas. Int J Oncol. 2005;26:369–77.
pubmed: 15645121
Zhang M, Wang B, Chong QY, Pandey V, Guo Z, Chen RM, et al. A novel small-molecule inhibitor of trefoil factor 3 (TFF3) potentiates MEK1/2 inhibition in lung adenocarcinoma. Oncogenesis 2019;8:65.
pubmed: 31685806
pmcid: 6828705
doi: 10.1038/s41389-019-0173-8
Wang XN, Wang SJ, Pandey V, Chen P, Li Q, Wu ZS, et al. Trefoil factor 3 as a novel biomarker to distinguish between adenocarcinoma and squamous cell carcinoma. Medicine. 2015;94:e860.
pubmed: 25997063
pmcid: 4602872
doi: 10.1097/MD.0000000000000860
Kannan N, Kang J, Kong X, Tang J, Perry JK, Mohankumar KM, et al. Trefoil factor 3 is oncogenic and mediates anti-estrogen resistance in human mammary carcinoma. Neoplasia 2010;12:1041–53.
pubmed: 21170268
pmcid: 3003139
doi: 10.1593/neo.10916
May FE, Westley BR. TFF3 is a valuable predictive biomarker of endocrine response in metastatic breast cancer. Endocr Relat Cancer. 2015;22:465–79.
pubmed: 25900183
pmcid: 4455223
doi: 10.1530/ERC-15-0129
Thomsen KG, Lyng MB, Elias D, Vever H, Knoop AS, Lykkesfeldt AE, et al. Gene expression alterations associated with outcome in aromatase inhibitor-treated ER
pubmed: 26585578
doi: 10.1007/s10549-015-3644-4
Garraway IP, Seligson D, Said J, Horvath S, Reiter RE. Trefoil factor 3 is overexpressed in human prostate cancer. Prostate 2004;61:209–14.
pubmed: 15368472
doi: 10.1002/pros.20096
Chong QY, You ML, Pandey V, Banerjee A, Chen YJ, Poh HM, et al. Release of HER2 repression of trefoil factor 3 (TFF3) expression mediates trastuzumab resistance in HER2
pubmed: 29088778
pmcid: 5650333
doi: 10.18632/oncotarget.18431
Poh HM, Chiou YS, Chong QY, Chen RM, Rangappa KS, Ma L, et al. Inhibition of TFF3 enhances sensitivity-and overcomes acquired resistance-to doxorubicin in estrogen receptor-positive mammary carcinoma. Cancers (Basel). 2019;11:1528.
doi: 10.3390/cancers11101528
Lau WH, Pandey V, Kong X, Wang XN, Wu Z, Zhu T, et al. Trefoil factor-3 (TFF3) stimulates de novo angiogenesis in mammary carcinoma both directly and indirectly via IL-8/CXCR2. PLoS One. 2015;10:e0141947.
pubmed: 26559818
pmcid: 4641663
doi: 10.1371/journal.pone.0141947
Morito K, Nakamura J, Kitajima Y, Kai K, Tanaka T, Kubo H, et al. The value of trefoil factor 3 expression in predicting the long-term outcome and early recurrence of colorectal cancer. Int J Oncol. 2015;46:563–8.
pubmed: 25405728
doi: 10.3892/ijo.2014.2755
Meng JR, Tang HZ, Zhou KZ, Shen WH, Guo HY. TFF3 and survivin expressions associate with a lower survival rate in gastric cancer. Clin Exp Med. 2013;13:297–303.
pubmed: 22996285
doi: 10.1007/s10238-012-0210-9
Ding A, Zhao W, Shi X, Yao R, Zhou F, Yue L, et al. Impact of NPM, TFF3 and TACC1 on the prognosis of patients with primary gastric cancer. PLoS One. 2013;8:e82136.
pubmed: 24358147
pmcid: 3864846
doi: 10.1371/journal.pone.0082136
Pandey V, Wu ZS, Zhang M, Li R, Zhang J, Zhu T, et al. Trefoil factor 3 promotes metastatic seeding and predicts poor survival outcome of patients with mammary carcinoma. Breast Cancer Res. 2014;16:429.
pubmed: 25266665
pmcid: 4303111
doi: 10.1186/s13058-014-0429-3
Terris B, Blaveri E, Crnogorac-Jurcevic T, Jones M, Missiaglia E, Ruszniewski P, et al. Characterization of gene expression profiles in intraductal papillary-mucinous tumors of the pancreas. Am J Pathol. 2002;160:1745–54.
pubmed: 12000726
pmcid: 1850868
doi: 10.1016/S0002-9440(10)61121-2
Jahan R, Ganguly K, Smith LM, Atri P, Carmicheal J, Sheinin Y, et al. Trefoil factor(s) and CA19.9: a promising panel for early detection of pancreatic cancer. EBioMedicine 2019;42:375–85.
pubmed: 30956167
pmcid: 6491718
doi: 10.1016/j.ebiom.2019.03.056
Cheng F, Su L, Yao C, Liu L, Shen J, Liu C, et al. SIRT1 promotes epithelial-mesenchymal transition and metastasis in colorectal cancer by regulating Fra-1 expression. Cancer Lett. 2016;375:274–83.
pubmed: 26975631
doi: 10.1016/j.canlet.2016.03.010
Tang JZ, Zuo ZH, Kong XJ, Steiner M, Yin Z, Perry JK, et al. Signal transducer and activator of transcription (STAT)-5A and STAT5B differentially regulate human mammary carcinoma cell behavior. Endocrinology 2010;151:43–55.
pubmed: 19966185
doi: 10.1210/en.2009-0651
Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG, National Centre for the Replacement, Refinement and Reduction of Amimals in Research. Animal research: reporting in vivo experiments-the ARRIVE guidelines. J Cereb Blood Flow Metab. 2011;31:991–3.
pubmed: 21206507
pmcid: 3070981
doi: 10.1038/jcbfm.2010.220
Pandey V, Wang B, Mohan CD, Raquib AR, Rangappa S, Srinivasa V, et al. Discovery of a small-molecule inhibitor of specific serine residue BAD phosphorylation. Proc Natl Acad Sci USA. 2018;115:E10505–E10514.
pubmed: 30309962
pmcid: 6217419
doi: 10.1073/pnas.1804897115
Jackerott M, Lee YC, Møllgård K, Kofod H, Jensen J, Rohleder S, et al. Trefoil factors are expressed in human and rat endocrine pancreas: differential regulation by growth hormone. Endocrinology 2006;147:5752–9.
pubmed: 16973727
doi: 10.1210/en.2006-0601
Fueger PT, Schisler JC, Lu D, Babu DA, Mirmira RG, Newgard CB, et al. Trefoil factor 3 stimulates human and rodent pancreatic islet beta-cell replication with retention of function. Mol Endocrinol. 2008;22:1251–9.
pubmed: 18258687
pmcid: 2366186
doi: 10.1210/me.2007-0500
Muskett FW, May FE, Westley BR, Feeney J. Solution structure of the disulfide-linked dimer of human intestinal trefoil factor (TFF3): the intermolecular orientation and interactions are markedly different from those of other dimeric trefoil proteins. Biochemistry 2003;42:15139–47.
pubmed: 14690424
doi: 10.1021/bi030182k
Hou P, Ma X, Zhang Q, Wu CJ, Liao W, Li J, et al. USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation. Genes Dev. 2019;33:1361–6.
pubmed: 31488580
pmcid: 6771391
doi: 10.1101/gad.326314.119
Zhan T, Ambrosi G, Wandmacher AM, Rauscher B, Betge J, Rindtorff N, et al. MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer. Nat Commun. 2019;10:2197.
pubmed: 31097693
pmcid: 6522484
doi: 10.1038/s41467-019-09898-0
Murillo-Garzón V, Kypta R. WNT signalling in prostate cancer. Nat Rev Urol. 2017;14:683–96.
pubmed: 28895566
doi: 10.1038/nrurol.2017.144
Wang VM, Ferreira RMM, Almagro J, Evan T, Legrave N, Zaw Thin M, et al. CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth. Nat Cell Biol. 2019;21:1425–35.
pubmed: 31685994
pmcid: 6944508
doi: 10.1038/s41556-019-0407-1
Zhang Z, Han H, Rong Y, Zhu K, Zhu Z, Tang Z, et al. Hypoxia potentiates gemcitabine-induced stemness in pancreatic cancer cells through AKT/Notch1 signaling. J Exp Clin Cancer Res. 2018;37:291.
pubmed: 30486896
pmcid: 6263055
doi: 10.1186/s13046-018-0972-3
Leung EY, Askarian-Amiri ME, Sarkar D, Ferraro-Peyret C, Joseph WR, Finlay GJ, et al. Endocrine therapy of estrogen receptor-positive breast cancer cells: early differential effects on stem cell markers. Front Oncol. 2017;7:184.
pubmed: 28929082
pmcid: 5591432
doi: 10.3389/fonc.2017.00184
Tang B, Yang Y, Kang M, Wang Y, Wang Y, Bi Y, et al. m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling. Mol Cancer. 2020;19:3.
pubmed: 31906946
pmcid: 6943907
doi: 10.1186/s12943-019-1128-6
Sun C, Fang Y, Yin J, Chen J, Ju Z, Zhang D, et al. Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers. Sci Transl Med. 2017;9:eaal5148.
pubmed: 28566428
pmcid: 5919217
doi: 10.1126/scitranslmed.aal5148
Kuninty PR, Bansal R, De Geus SWL, Mardhian DF, Schnittert J, van Baarlen J, et al. ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer. Sci Adv. 2019;5:eaax2770.
pubmed: 31517053
pmcid: 6726450
doi: 10.1126/sciadv.aax2770
Liu W, Mao Y, Zhang X, Wang Y, Wu J, Zhao S, et al. RGDV-modified gemcitabine: a nano-medicine capable of prolonging half-life, overcoming resistance and eliminating bone marrow toxicity of gemcitabine. Int J Nanomed. 2019;14:7263–79.
doi: 10.2147/IJN.S212978
Ma T, Chen W, Zhi X, Liu H, Zhou Y, Chen BW, et al. USP9X inhibition improves gemcitabine sensitivity in pancreatic cancer by inhibiting autophagy. Cancer Lett. 2018;436:129–38.
pubmed: 30118840
doi: 10.1016/j.canlet.2018.08.010
Nakajima EC, Drezner N, Li X, Mishra-Kalyani PS, Liu Y, Zhao H, et al. FDA approval summary: sotorasib for KRAS G12C-mutated metastatic NSCLC. Clin Cancer Res. 2021; https://doi.org/10.1158/1078-0432.CCR-21-3074 .
Krishnamurthy N, Kurzrock R. Targeting the Wnt/beta-catenin pathway in cancer: update on effectors and inhibitors. Cancer Treat Rev. 2018;62:50–60.
pubmed: 29169144
doi: 10.1016/j.ctrv.2017.11.002
Dotan E, Cardin DB, Lenz HJ, Messersmith W, O’Neil B, Cohen SJ, et al. Phase Ib study of Wnt inhibitor ipafricept with gemcitabine and nab-paclitaxel in patients with previously untreated stage IV pancreatic cancer. Clin Cancer Res. 2020;26:5348–57.
pubmed: 32694153
pmcid: 7572624
doi: 10.1158/1078-0432.CCR-20-0489