Abstract
Pancreatic cancer is regarded as the most lethal solid tumor worldwide. Deregulated and constitutively activated NF-κB signaling is one of the major characteristics of pancreatic cancer. The total expression level and subcellular localization of RelA/p65 have been shown to determine the activation of canonical NF-κB signaling in pancreatic cancer. FGD3, which is involved in regulating the actin cytoskeleton and cell shape, has been reported to inhibit cancer cell migration and predict a favorable prognosis in multiple types of cancer. However, the specific role of FGD3 in pancreatic cancer is still unknown. In this study, we conducted a systematic investigation of the cancer-related role of FGD3 in pancreatic cancer. We demonstrated that FGD3 was abnormally downregulated in pancreatic cancer tissues and that low expression of FGD3 was associated with unfavorable prognosis in patients with pancreatic cancer. Then, we showed that FGD3 inhibited pancreatic cancer cell proliferation, invasion and metastasis in vivo and in vitro. Moreover, we revealed that FGD3 silencing activated the NF-κB signaling pathway by promoting HSF4 nuclear translocation and increasing p65 expression in pancreatic cancer cells. Therefore, our results identified a novel and targetable FGD3/HSF4/p65 signaling axis in pancreatic cancer cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding authors (Xin Jin, jinxinxy2@csu.edu.cn) on reasonable request.
References
Khalaf N, El-Serag HB, Abrams HR, Thrift AP. Burden of pancreatic cancer: from epidemiology to practice. Clin Gastroenterol Hepatol. 2021;19:876–84.
Kabacaoglu D, Ruess DA, Ai J, Algul H. NF-kappaB/rel transcription factors in pancreatic cancer: focusing on RelA, c-Rel, and RelB. Cancers (Basel) 2019;11:937.
Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest. 2015;125:3335–7.
Cable J, Greenbaum B, Pe’er D, Bollard CM, Bruni S, Griffin ME, et al. Frontiers in cancer immunotherapy-a symposium report. Ann N. Y Acad Sci. 2021;1489:30–47.
Wu J, Cai J. Dilemma and challenge of immunotherapy for pancreatic cancer. Dig Dis Sci. 2021;66:359–68.
Dougan SK. The pancreatic cancer microenvironment. Cancer J. 2017;23:321–5.
Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007;67:9518–27.
Hanson JL, Hawke NA, Kashatus D, Baldwin AS. The nuclear factor kappaB subunits RelA/p65 and c-Rel potentiate but are not required for Ras-induced cellular transformation. Cancer Res. 2004;64:7248–55.
Finco TS, Westwick JK, Norris JL, Beg AA, Der CJ, Baldwin AS Jr. Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation. J Biol Chem. 1997;272:24113–6.
Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, et al. KrasG12D-induced IKK2/beta/NF-kappaB activation by IL-1alpha and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:105–20.
Makieva S, Dubicke A, Rinaldi SF, Fransson E, Ekman-Ordeberg G, Norman JE. The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes. Am J Obstet Gynecol. 2017;216:602 e601–602 e621.
Nakanishi H, Takai Y. Frabin and other related Cdc42-specific guanine nucleotide exchange factors couple the actin cytoskeleton with the plasma membrane. J Cell Mol Med. 2008;12:1169–76.
Willis S, Sun Y, Abramovitz M, Fei T, Young B, Lin X, et al. High expression of FGD3, a putative regulator of cell morphology and motility, is prognostic of favorable outcome in multiple cancers. JCO Precis Oncol. 2017;1: PO.17.00009.
Susini T, Renda I. FGD3 gene as a new prognostic factor in breast cancer. Anticancer Res. 2020;40:3645–9.
Renda I, Bianchi S, Vezzosi V, Nori J, Vanzi E, Tavella K, et al. Expression of FGD3 gene as prognostic factor in young breast cancer patients. Sci Rep. 2019;9:15204.
Ma C, Li H, Li X, Lu S, He J. The prognostic value of faciogenital dysplasias as biomarkers in head and neck squamous cell carcinoma. Biomark Med. 2019;13:1399–415.
Jing B, Qian R, Jiang D, Gai Y, Liu Z, Guo F, et al. Extracellular vesicles-based pre-targeting strategy enables multi-modal imaging of orthotopic colon cancer and image-guided surgery. J Nanobiotechnology. 2021;19:151.
Jing B, Gai Y, Qian R, Liu Z, Zhu Z, Gao Y, et al. Hydrophobic insertion-based engineering of tumor cell-derived exosomes for SPECT/NIRF imaging of colon cancer. J Nanobiotechnology. 2021;19:7.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.
Walter W, Sanchez-Cabo F, Ricote M. GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics. 2015;31:2912–4.
Yan J, Enge M, Whitington T, Dave K, Liu J, Sur I, et al. Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites. Cell. 2013;154:801–13.
Fan P, Zhao J, Meng Z, Wu H, Wang B, Wu H, et al. Overexpressed histone acetyltransferase 1 regulates cancer immunity by increasing programmed death-ligand 1 expression in pancreatic cancer. J Exp Clin Cancer Res. 2019;38:47.
Chen R, Liliental JE, Kowalski PE, Lu Q, Cohen SN. Regulation of transcription of hypoxia-inducible factor-1alpha (HIF-1alpha) by heat shock factors HSF2 and HSF4. Oncogene. 2011;30:2570–80.
Neumann M, Naumann M. Beyond IkappaBs: alternative regulation of NF-kappaB activity. FASEB J. 2007;21:2642–54.
Aggarwal BB. Nuclear factor-kappaB: the enemy within. Cancer Cell. 2004;6:203–8.
Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ. The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res. 1999;5:119–27.
Rayet B, Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999;18:6938–47.
Kong R, Sun B, Jiang H, Pan S, Chen H, Wang S, et al. Downregulation of nuclear factor-kappaB p65 subunit by small interfering RNA synergizes with gemcitabine to inhibit the growth of pancreatic cancer. Cancer Lett. 2010;291:90–8.
Pan X, Arumugam T, Yamamoto T, Levin PA, Ramachandran V, Ji B, et al. Nuclear factor-kappaB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells. Clin Cancer Res. 2008;14:8143–51.
Matsuo Y, Sawai H, Funahashi H, Takahashi H, Sakamoto M, Yamamoto M, et al. Enhanced angiogenesis due to inflammatory cytokines from pancreatic cancer cell lines and relation to metastatic potential. Pancreas. 2004;28:344–52.
Wang L, Wu H, Wang L, Zhang H, Lu J, Liang Z, et al. Asporin promotes pancreatic cancer cell invasion and migration by regulating the epithelial-to-mesenchymal transition (EMT) through both autocrine and paracrine mechanisms. Cancer Lett. 2017;398:24–36.
Azoitei N, Becher A, Steinestel K, Rouhi A, Diepold K, Genze F, et al. PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation. Mol Cancer. 2016;15:3.
Meng Q, Liang C, Hua J, Zhang B, Liu J, Zhang Y, et al. A miR-146a-5p/TRAF6/NF-kB p65 axis regulates pancreatic cancer chemoresistance: functional validation and clinical significance. Theranostics. 2020;10:3967–79.
Wang L, Zhou W, Zhong Y, Huo Y, Fan P, Zhan S, et al. Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-kappaB signaling pathway. Mol Cancer. 2017;16:61.
Jin X, Ding D, Yan Y, Li H, Wang B, Ma L, et al. Phosphorylated RB promotes cancer immunity by inhibiting NF-kappaB activation and PD-L1 expression. Mol Cell. 2019;73:22–35 e26.
Abane R, Mezger V. Roles of heat shock factors in gametogenesis and development. FEBS J. 2010;277:4150–72.
Fujimoto M, Izu H, Seki K, Fukuda K, Nishida T, Yamada S, et al. HSF4 is required for normal cell growth and differentiation during mouse lens development. EMBO J. 2004;23:4297–306.
Shi X, Cui B, Wang Z, Weng L, Xu Z, Ma J, et al. Removal of Hsf4 leads to cataract development in mice through down-regulation of gamma S-crystallin and Bfsp expression. BMC Mol Biol. 2009;10:10.
Liao S, Qu Z, Li L, Zhou B, Gao M, Huang M, et al. HSF4 transcriptional regulates HMOX-1 expression in HLECs. Gene. 2018;655:30–4.
Cui X, Zhang J, Du R, Wang L, Archacki S, Zhang Y, et al. HSF4 is involved in DNA damage repair through regulation of Rad51. Biochim Biophys Acta. 2012;1822:1308–15.
Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S. Heat shock proteins and cancer. Trends Pharm Sci. 2017;38:226–56.
Yang Y, Jin L, Zhang J, Wang J, Zhao X, Wu G, et al. High HSF4 expression is an independent indicator of poor overall survival and recurrence free survival in patients with primary colorectal cancer. IUBMB Life. 2017;69:956–61.
Jin X, Eroglu B, Cho W, Yamaguchi Y, Moskophidis D, Mivechi NF. Inactivation of heat shock factor Hsf4 induces cellular senescence and suppresses tumorigenesis in vivo. Mol Cancer Res. 2012;10:523–34.
Ma P, Tang WG, Hu JW, Hao Y, Xiong LK, Wang MM, et al. HSP4 triggers epithelial-mesenchymal transition and promotes motility capacities of hepatocellular carcinoma cells via activating AKT. Liver Int. 2020;40:1211–23.
Pasteris NG, Nagata K, Hall A, Gorski JL. Isolation, characterization, and mapping of the mouse Fgd3 gene, a new Faciogenital Dysplasia (FGD1; Aarskog Syndrome) gene homologue. Gene. 2000;242:237–47.
Oshima T, Fujino T, Ando K, Hayakawa M. Proline-rich domain plays a crucial role in extracellular stimuli-responsive translocation of a Cdc42 guanine nucleotide exchange factor, FGD1. Biol Pharm Bull. 2010;33:35–9.
Wu W, Jing D, Meng Z, Hu B, Zhong B, Deng X, et al. FGD1 promotes tumor progression and regulates tumor immune response in osteosarcoma via inhibiting PTEN activity. Theranostics. 2020;10:2859–71.
Funding
This work was supported by grants from the National Natural Science Foundation of China (Grant No. 82073178 (H.W.), Grant No. 82073321 (X.J.)) and Science Foundation of Ministry of Education of China (Grant No. 2172019kfyRCPY069 (X.J.)).
Author information
Authors and Affiliations
Contributions
XJ: funding acquisition, investigation, methodology, project administration, writing - original draft. HW: funding acquisition, project administration, writing - original draft. BJ: PET-CT imaging and analysis. XC: conceptualization, supervision, project administration. FG: software, formal analysis, methodology.
Corresponding authors
Ethics declarations
Consent for publication
All subjects have written informed consent.
Competing interests
The authors declare no competing interests.
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
Guo, F., Cheng, X., Jing, B. et al. FGD3 binds with HSF4 to suppress p65 expression and inhibit pancreatic cancer progression. Oncogene 41, 838–851 (2022). https://doi.org/10.1038/s41388-021-02140-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-021-02140-6
This article is cited by
-
Stabilization of KPNB1 by deubiquitinase USP7 promotes glioblastoma progression through the YBX1-NLGN3 axis
Journal of Experimental & Clinical Cancer Research (2024)