The poor prognosis of gastric cancer (GC) results largely from metastasis and chemotherapy resistance. Toward novel therapeutic strategies that target or evade these phenomena, we evaluated the function of the transcriptional regulator transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) in GC cells, including stem-like cells. In this study, the correlation of expression of TBL1XR1 and clinical features and GC patients’ outcomes was evaluated. Knockdown or exogenous expression of TBL1XR1 was combined with in vitro (2D and 3D cultures) and in vivo (mouse lung and lymphatic metastasis models) assays to evaluate the function of TBL1XR1. TBL1XR1’s downstream signaling was delineated by phospho-kinase array and knockdown of candidate mediators. Analysis of clinical data showed that TBL1XR1 overexpression was correlated with worse prognosis. Functional assays showed that TBL1XR1 promoted stemness, epithelial–mesenchymal transition (EMT), and lung and lymphatic metastasis in GC cells. TBL1XR1 activated ERK1/2-Sox2 signaling and was dependent on signaling via PI3K/AKT, in GC stem-like cells distinguished by CD44 expression. Moreover, inhibition of these signaling proteins reversed chemoresistance in in vitro and in vivo models. Taken together, our results indicate that TBL1XR1 promotes stemness and metastasis in GC, making it a potential prognostic indicator. The PI3K/AKT-TBL1XR1-ERK1/2-Sox2 axis may represent a target for the treatment of GC.
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AKAP8L enhances the stemness and chemoresistance of gastric cancer cells by stabilizing SCD1 mRNA
Cell Death & Disease Open Access 15 December 2022
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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
Zhang H, Jiang H, Zhang H, Liu J, Hu X, Chen L. Ribophorin II potentiates P-glycoprotein- and ABCG2-mediated multidrug resistance via activating ERK pathway in gastric cancer. Int J Biol Macromol. 2019;128:574–82.
Dawood S, Austin L, Cristofanilli M. Cancer stem cells: implications for cancer therapy. Oncology. 2014;28:1101–7, 1110.
Garcia-Mayea Y, Mir C, Masson F, Paciucci R, ME LL. Insights into new mechanisms and models of cancer stem cell multidrug resistance. Semin Cancer Biol. 2019.
Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem cells. 2009;27:1006–20.
Yoon C, Park DJ, Schmidt B, Thomas NJ, Lee HJ, Kim TS, et al. CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance. Clin Cancer Res. 2014;20:3974–88.
Bekaii-Saab T, El-Rayes B. Identifying and targeting cancer stem cells in the treatment of gastric cancer. Cancer. 2017;123:1303–12.
Nguyen PH, Giraud J, Chambonnier L, Dubus P, Wittkop L, Belleannee G, et al. Characterization of biomarkers of tumorigenic and chemoresistant cancer stem cells in human gastric carcinoma. Clin Cancer Res. 2017;23:1586–97.
Han ME, Jeon TY, Hwang SH, Lee YS, Kim HJ, Shim HE, et al. Cancer spheres from gastric cancer patients provide an ideal model system for cancer stem cell research. Cell Mol Life Sci. 2011;68:3589–605.
Zhang J, Kalkum M, Chait BT, Roeder RG. The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Mol Cell. 2002;9:611–23.
Li X, Liang W, Liu J, Lin C, Wu S, Song L, et al. Transducin (beta)-like 1 X-linked receptor 1 promotes proliferation and tumorigenicity in human breast cancer via activation of beta-catenin signaling. Breast cancer Res. 2014;16:465.
Liu L, Lin C, Liang W, Wu S, Liu A, Wu J, et al. TBL1XR1 promotes lymphangiogenesis and lymphatic metastasis in esophageal squamous cell carcinoma. Gut. 2015;64:26–36.
Chen SP, Yang Q, Wang CJ, Zhang LJ, Fang Y, Lei FY, et al. Transducin beta-like 1 X-linked receptor 1 suppresses cisplatin sensitivity in nasopharyngeal carcinoma via activation of NF-kappaB pathway. Mol Cancer. 2014;13:195.
Zhou Q, Wang X, Yu Z, Wu X, Chen X, Li J, et al. Transducin (beta)-like 1 X-linked receptor 1 promotes gastric cancer progression via the ERK1/2 pathway. Oncogene. 2017;36:1873–86.
Choi HK, Choi KC, Yoo JY, Song M, Ko SJ, Kim CH, et al. Reversible SUMOylation of TBL1-TBLR1 regulates beta-catenin-mediated Wnt signaling. Mol Cell. 2011;43:203–16.
Wang J, Ou J, Guo Y, Dai T, Li X, Liu J, et al. TBLR1 is a novel prognostic marker and promotes epithelial-mesenchymal transition in cervical cancer. Br J Cancer. 2014;111:112–24.
Xi X, Wu Q, Bao Y, Lin M, Zhong X, Dai X, et al. Overexpression of TBL1XR1 confers tumorigenic capability and promotes recurrence of osteosarcoma. Eur J Pharmacol. 2019;844:259–67.
Etoh T, Inoue H, Tanaka S, Barnard GF, Kitano S, Mori M. Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res. 2001;61:2145–53.
Hao S, Yang Y, Liu Y, Yang S, Wang G, Xiao J, et al. JAM-C promotes lymphangiogenesis and nodal metastasis in non-small cell lung cancer. Tumour Biol. 2014;35:5675–87.
Herrera B, van Dinther M, Ten Dijke P, Inman GJ. Autocrine bone morphogenetic protein-9 signals through activin receptor-like kinase-2/Smad1/Smad4 to promote ovarian cancer cell proliferation. Cancer Res. 2009;69:9254–62.
Hu J, Ye H, Fu A, Chen X, Wang Y, Chen X, et al. Deguelin–an inhibitor to tumor lymphangiogenesis and lymphatic metastasis by downregulation of vascular endothelial cell growth factor-D in lung tumor model. Int J Cancer. 2010;127:2455–66.
Khromova N, Kopnin P, Rybko V, Kopnin BP. Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms. Oncogene. 2012;31:1389–97.
Mashino K, Sadanaga N, Yamaguchi H, Tanaka F, Ohta M, Shibuta K, et al. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res. 2002;62:2937–41.
Nasarre P, Gemmill RM, Potiron VA, Roche J, Lu X, Baron AE, et al. Neuropilin-2 Is upregulated in lung cancer cells during TGF-beta1-induced epithelial-mesenchymal transition. Cancer Res. 2013;73:7111–21.
Ono H, Imoto I, Kozaki K, Tsuda H, Matsui T, Kurasawa Y, et al. SIX1 promotes epithelial-mesenchymal transition in colorectal cancer through ZEB1 activation. Oncogene. 2012;31:4923–34.
Skog M, Bono P, Lundin M, Lundin J, Louhimo J, Linder N, et al. Expression and prognostic value of transcription factor PROX1 in colorectal cancer. Br J Cancer. 2011;105:1346–51.
Turk CM, Fagan-Solis KD, Williams KE, Gozgit JM, Smith-Schneider S, Marconi SA, et al. Paralemmin-1 is over-expressed in estrogen-receptor positive breast cancers. Cancer cell Int. 2012;12:17.
Wildi S, Kleeff J, Maruyama H, Maurer CA, Buchler MW, Korc M. Overexpression of activin A in stage IV colorectal cancer. Gut. 2001;49:409–17.
Zaytseva YY, Rychahou PG, Gulhati P, Elliott VA, Mustain WC, O’Connor K, et al. Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res. 2012;72:1504–17.
Xia P, Xu XY. PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application. Am J Cancer Res. 2015;5:1602–9.
Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C, et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA. 2009;106:268–73.
Wang YK, Zhu YL, Qiu FM, Zhang T, Chen ZG, Zheng S, et al. Activation of Akt and MAPK pathways enhances the tumorigenicity of CD133+ primary colon cancer cells. Carcinogenesis. 2010;31:1376–80.
Yoon C, Cho SJ, Aksoy BA, Park do J, Schultz N, Ryeom SW, et al. Chemotherapy resistance in diffuse-type gastric adenocarcinoma is mediated by RhoA activation in cancer stem-like cells. Clin Cancer Res. 2016;22:971–83.
Till JE, Yoon C, Kim BJ, Roby K, Addai P, Jonokuchi E, et al. Oncogenic KRAS and p53 loss drive gastric tumorigenesis in mice that can be attenuated by E-cadherin expression. Cancer Res. 2017;77:5349–59.
Lee KM, Giltnane JM, Balko JM, Schwarz LJ, Guerrero-Zotano AL, Hutchinson KE, et al. MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab. 2017;26:633–.e637.
Samanta D, Gilkes DM, Chaturvedi P, Xiang L, Semenza GL. Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proc Natl Acad Sci USA. 2014;111:E5429–38.
Ruan X, Liu A, Zhong M, Wei J, Zhang W, Rong Y, et al. Silencing LGR6 attenuates stemness and chemoresistance via inhibiting Wnt/beta-catenin signaling in ovarian cancer. Mol Ther Oncolytics. 2019;14:94–106.
An Y, Wang B, Wang X, Dong G, Jia J, Yang Q. SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop. Cell Death Dis. 2020;11:115.
Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017;14:611–29.
Sciacovelli M, Frezza C. Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer. FEBS J. 2017;284:3132–44.
Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2001;17:615–75.
Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer. 2019;18:26.
Martelli AM, Evangelisti C, Follo MY, Ramazzotti G, Fini M, Giardino R, et al. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells. Curr Med Chem. 2011;18:2715–26.
Martins-Neves SR, Cleton-Jansen AM, Gomes CMF. Therapy-induced enrichment of cancer stem-like cells in solid human tumors: Where do we stand? Pharmacol Res. 2018;137:193–204.
Dong H, Liu H, Zhou W, Zhang F, Li C, Chen J, et al. GLI1 activation by non-classical pathway integrin alphavbeta3/ERK1/2 maintains stem cell-like phenotype of multicellular aggregates in gastric cancer peritoneal metastasis. Cell Death Dis. 2019;10:574.
Khurana SS, Riehl TE, Moore BD, Fassan M, Rugge M, Romero-Gallo J, et al. The hyaluronic acid receptor CD44 coordinates normal and metaplastic gastric epithelial progenitor cell proliferation. J Biol Chem. 2013;288:16085–97.
Salaroglio IC, Mungo E, Gazzano E, Kopecka J, Riganti C. ERK is a pivotal player of chemo-immune-resistance in cancer. Int J Mol Sci. 2019;20.
Zhou L, Li X, Zhou F, Jin Z, Chen D, Wang P, et al. Downregulation of leucine-rich repeats and immunoglobulin-like domains 1 by microRNA-20a modulates gastric cancer multidrug resistance. Cancer Sci. 2018;109:1044–54.
Huang W, Wan C, Luo Q, Huang Z, Luo Q. Genistein-inhibited cancer stem cell-like properties and reduced chemoresistance of gastric cancer. Int J Mol Sci. 2014;15:3432–43.
Zhao YY, Yu L, Liu BL, He XJ, Zhang BY. Downregulation of P-gp, Ras and p-ERK1/2 contributes to the arsenic trioxide-induced reduction in drug resistance towards doxorubicin in gastric cancer cell lines. Mol Med Rep. 2015;12:7335–43.
Liu SQ, Yu JP, Yu HG, Lv P, Chen HL. Activation of Akt and ERK signalling pathways induced by etoposide confer chemoresistance in gastric cancer cells. Digestive Liver Dis. 2006;38:310–8.
Wu G, Qin XQ, Guo JJ, Li TY, Chen JH. AKT/ERK activation is associated with gastric cancer cell resistance to paclitaxel. Int J Clin Exp Pathol. 2014;7:1449–58.
Ji R, Zhang B, Zhang X, Xue J, Yuan X, Yan Y, et al. Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer. Cell Cycle. 2015;14:2473–83.
Zhang JX, Xu Y, Gao Y, Chen C, Zheng ZS, Yun M, et al. Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway. Mol Cancer. 2017;16:18.
Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl J Med. 2012;367:107–14.
Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 2013;14:134–40.
Banerjee A, Jakacki RI, Onar-Thomas A, Wu S, Nicolaides T, Young Poussaint T, et al. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro-Oncol. 2017;19:1135–44.
Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017;8:CD004064.
Lu J, Xu BB, Zheng ZF, Xie JW, Wang JB, Lin JX, et al. CRP/prealbumin, a novel inflammatory index for predicting recurrence after radical resection in gastric cancer patients: post hoc analysis of a randomized phase III trial. Gastric Cancer. 2019;22:536–45.
UKCCCR guidelines for the use of cell lines in cancer research. Br J Cancer. 2000;82:1495–509.
Cho SJ, Yoon C, Lee JH, Chang KK, Lin JX, Kim YH, et al. KMT2C mutations in diffuse-type gastric adenocarcinoma promote epithelial-to-mesenchymal transition. Clin Cancer Res. 2018;24:6556–69.
Bisson I, Prowse DM. WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res. 2009;19:683–97.
Yoon SS, Eto H, Lin CM, Nakamura H, Pawlik TM, Song SU, et al. Mouse endostatin inhibits the formation of lung and liver metastases. Cancer Res. 1999;59:6251–6.
Cho SJ, Kook MC, Lee JH, Shin JY, Park J, Bae YK, et al. Peroxisome proliferator-activated receptor gamma upregulates galectin-9 and predicts prognosis in intestinal-type gastric cancer. Int J Cancer. 2015;136:810–20.
Yoon C, Till J, Cho SJ, Chang KK, Lin JX, Huang CM, et al. KRAS activation in gastric adenocarcinoma stimulates epithelial-to-mesenchymal transition to cancer stem-like cells and promotes metastasis. Mol cancer Res. 2019;17:1945–57.
This research was supported by NIH/NCI through 1R01 CA158301-01 (SSY), Cancer Center Support Grant P30 CA008748 (MSKCC), and Natural Science Foundation of Fujian Province (2019J01155). Authors thank Jessica Moore, MS, senior editor and grant writer at MSK, for help in editing and revising the manuscript.
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Lu, J., Bang, H., Kim, S.M. et al. Lymphatic metastasis-related TBL1XR1 enhances stemness and metastasis in gastric cancer stem-like cells by activating ERK1/2-SOX2 signaling. Oncogene 40, 922–936 (2021). https://doi.org/10.1038/s41388-020-01571-x
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AKAP8L enhances the stemness and chemoresistance of gastric cancer cells by stabilizing SCD1 mRNA
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