Tumor-suppressive microRNA-551b-3p targets H6PD to inhibit gallbladder cancer progression


Gallbladder cancer (GBC) is a highly malignant cancer with poor prognosis. Extensive studies have reported the vital functionality of several microRNAs (miRNAs) in numerous human cancers, including GBC. Microarray analysis has identified the differentially expressed miR-551b-3p in GBC. Therefore, this study aims to validate the underlying mechanism by which miR-551b-3p participated in epithelial–mesenchymal transition (EMT), invasion and migration of GBCs. Bioinformatic analysis predicted the binding of miR-551b-3p to H6PD. We validated the reduced miR-551b-3p expression and increased H6PD expression in the GBC tissues and GBC cell lines. Artificial modulation of miR-551b-3p and H6PD (down- and upregulation) was conducted to explore their roles in EMT, invasive, and migratory abilities of GBCs, and the tumor-bearing mice were used to determine tumor growth. Overexpression of miR-551b-3p or silencing of H6PD was observed to suppress the expressions of N-cadherin and vimentin, and to promote the expression of E-cadherin, along with reduced invasive and migratory ability of GBCs. Mechanistically, miR-551b-3p could evidently target and inhibit the expression of H6PD. Moreover, in vivo experiments substantiated the tumor-inhibiting activities of miR-551b-3p in nude mice. Conjointly, our study suggests that overexpression of miR-551b-3p inhibited the EMT, migration, and invasion of GBCs by inhibiting the expression of H6PD, indicating that miR-551b-3p may serve as a potential target for future development of therapeutic strategies for GBC.

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Fig. 1: MiR-551b-3p is involved in the regulation of GBCs by monitoring H6PD expression.
Fig. 2: miR-551b-3p expresses lower while H6PD expresses higher in GBC tissues and cells than in chronic cholecystitis tissues and HGBECs.
Fig. 3: miR-551b-3p overexpression inhibits EMT of GBCs.
Fig. 4: miR-551b-3p negatively inhibits H6PD expression.
Fig. 5: H6PD silencing inhibits EMT, invasion, and migration of GBCs.
Fig. 6: Inhibition of EMT, migration, and invasion of GBCs through upregulation of miR-551b-3p could be reversed by upregulating H6PD expression in vitro.
Fig. 7: Inhibition of EMT, migration, and invasion of GBCs through upregulation of miR-551b-3p could be reversed by upregulating H6PD expression in vivo.
Fig. 8: Mechanism hypothesis diagram.

Data availability

The data sets generated and/or analysed during the current study are available from the corresponding author on reasonable request.


  1. 1.

    Tadokoro T, Morishita A, Fujihara S, Iwama H, Niki T, Fujita K, et al. Galectin-9: an anticancer molecule for gallbladder carcinoma. Int J Oncol. 2016;48:1165–74.

    CAS  Article  Google Scholar 

  2. 2.

    Jang JY, Heo JS, Han Y, Chang J, Kim JR, Kim H, et al. Impact of type of surgery on survival outcome in patients with early gallbladder cancer in the era of minimally invasive surgery: oncologic safety of laparoscopic surgery. Med (Baltim). 2016;95:e3675.

    Article  Google Scholar 

  3. 3.

    Atanasova S, Kamin T, Petric G. Exploring the benefits and challenges of health professionals’ participation in online health communities: Emergence of (dis)empowerment processes and outcomes. Int J Med Inf. 2017;98:13–21.

    Article  Google Scholar 

  4. 4.

    Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;118:1591–602.

    CAS  Article  Google Scholar 

  5. 5.

    Dwivedi AN, Jain S, Dixit R. Gall bladder carcinoma: aggressive malignancy with protean loco-regional and distant spread. World J Clin Cases. 2015;3:231–44.

    Article  Google Scholar 

  6. 6.

    Li Z, Yu X, Shen J, Law PT, Chan MT, Wu WK. MicroRNA expression and its implications for diagnosis and therapy of gallbladder cancer. Oncotarget 2015;6:13914–21.

    Article  Google Scholar 

  7. 7.

    He S, Wang G, Ni J, Zhuang J, Zhuang S, Wang G, et al. MicroRNA-511 inhibits cellular proliferation and invasion in colorectal cancer by directly targeting hepatoma-derived growth factor. Oncol Res. 2018;26:1355–63.

  8. 8.

    Chaluvally-Raghavan P, Jeong KJ, Pradeep S, Silva AM, Yu S, Liu W, et al. Direct upregulation of STAT3 by MicroRNA-551b-3p deregulates growth and metastasis of ovarian cancer. Cell Rep. 2016;15:1493–504.

    CAS  Article  Google Scholar 

  9. 9.

    Yuan H, Chen Z, Bai S, Wei H, Wang Y. Ji R, et al. Molecular mechanisms of lncRNA SMARCC2/miR-551b-3p/TMPRSS4 axis in gastric cancer. Cancer Lett. 2018;418:84–96.

    CAS  Article  Google Scholar 

  10. 10.

    Tsachaki M, Mladenovic N, Stambergova H, Birk J, Odermatt A. Hexose-6-phosphate dehydrogenase controls cancer cell proliferation and migration through pleiotropic effects on the unfolded-protein response, calcium homeostasis, and redox balance. FASEB J. 2018;32:2690–705.

    Article  Google Scholar 

  11. 11.

    Hewitt KN, Walker EA, Stewart PM. Minireview: hexose-6-phosphate dehydrogenase and redox control of 11{beta}-hydroxysteroid dehydrogenase type 1 activity. Endocrinology 2005;146:2539–43.

    CAS  Article  Google Scholar 

  12. 12.

    White PC, Rogoff D, McMillan DR, Lavery GG. Hexose 6-phosphate dehydrogenase (H6PD) and corticosteroid metabolism. Mol Cell Endocrinol. 2007;265-266:89–92.

    CAS  Article  Google Scholar 

  13. 13.

    Chen Z, Liu X, Hu Z, Wang Y, Liu M, Liu X, et al. Identification and characterization of tumor suppressor and oncogenic miRNAs in gastric cancer. Oncol Lett. 2015;10:329–36.

    CAS  Article  Google Scholar 

  14. 14.

    Chen Z, Liu X, Liu M, Liu X, Jia J, Ji R, et al. [Expression of miR-551b-3p in gastric cancer cell lines and tissues and its clinical significance]. Zhonghua Zhong Liu Za Zhi. 2014;36:903–4.

  15. 15.

    Galbraith L, Leung HY, Ahmad I. Lipid pathway deregulation in advanced prostate cancer. Pharm Res. 2018;131:177–84.

    CAS  Article  Google Scholar 

  16. 16.

    Yuan T, Yang Y, Chen J, Li W, Li W, Zhang Q, et al. Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD. Leukemia 2017;31:2355–64.

    CAS  Article  Google Scholar 

  17. 17.

    Bu Q, You F, Pan G, Yuan Q, Cui T, Hao L, et al. MiR-125b inhibits anaplastic thyroid cancer cell migration and invasion by targeting PIK3CD. Biomed Pharmacother. 2017;88:443–8.

    CAS  Article  Google Scholar 

  18. 18.

    Hu HB, Chen Q, Ding SQ. LncRNA LINC01116 competes with miR-145 for the regulation of ESR1 expression in breast cancer. Eur Rev Med Pharm Sci. 2018;22:1987–93.

    Google Scholar 

  19. 19.

    Gu L, Lu LS, Zhou DL, Liu ZC. UCA1 promotes cell proliferation and invasion of gastric cancer by targeting CREB1 sponging to miR-590-3p. Cancer Med. 2018;7:1253–63.

    CAS  Article  Google Scholar 

  20. 20.

    Croce CM, Calin GA. miRNAs, cancer, and stem cell division. Cell 2005;122:6–7.

    CAS  Article  Google Scholar 

  21. 21.

    Liu G, Zhu J, Yu M, Cai C, Zhou Y, Yu M, et al. Glutamate dehydrogenase is a novel prognostic marker and predicts metastases in colorectal cancer patients. J Transl Med. 2015;13:144.

    Article  Google Scholar 

  22. 22.

    Zhang JWG, Mao Q. Glutamate dehydrogenase (GDH) regulates bioenergetics and redox homeostasis in human glioma. Oncotarget 2016;295:799–800.

    Google Scholar 

  23. 23.

    Cai Q, Wang Z, Wang S, Weng M, Zhou D, Li C, et al. Long non-coding RNA LINC00152 promotes gallbladder cancer metastasis and epithelial-mesenchymal transition by regulating HIF-1alpha via miR-138. Open Biol. 2017;7160247.

  24. 24.

    Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 2013;19:1438–49.

    CAS  Article  Google Scholar 

  25. 25.

    Nakajima S, Doi R, Toyoda E, Tsuji S, Wada M, Koizumi M, et al. N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res. 2004;10:4125–33.

    CAS  Article  Google Scholar 

  26. 26.

    Nieman MT, Prudoff RS, Johnson KR, Wheelock MJ. N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol. 1999;147:631–44.

    CAS  Article  Google Scholar 

  27. 27.

    Song G, Zhang H, Chen C, Gong L, Chen B, Zhao S, et al. miR-551b regulates epithelial-mesenchymal transition and metastasis of gastric cancer by inhibiting ERBB4 expression. Oncotarget 2017;8:45725–35.

    Article  Google Scholar 

  28. 28.

    Su Z, Liu G, Fang T, Zhang K, Yang S, Zhang H, et al. Expression and prognostic value of glutamate dehydrogenase in extrahepatic cholangiocarcinoma patients. Am J Transl Res. 2017;9:2106–18.

    CAS  PubMed  PubMed Central  Google Scholar 

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We give our sincere gratitude to the reviewers for their valuable suggestions.

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Tao Ji, Lijun Gao, and Zongbu Yu wrote the main manuscript text, Tao Ji collected the data, and Lijun Gao prepared all tables. All authors reviewed the manuscript.

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Correspondence to Zongbu Yu.

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Ji, T., Gao, L. & Yu, Z. Tumor-suppressive microRNA-551b-3p targets H6PD to inhibit gallbladder cancer progression. Cancer Gene Ther (2020). https://doi.org/10.1038/s41417-020-00252-x

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