International Ophthalmology

, Volume 39, Issue 12, pp 2825–2832 | Cite as

Higher expression of cation transport regulator-like protein 1 (CHAC1) predicts of poor outcomes in uveal melanoma (UM) patients

  • Yanchen Liu
  • Mengyun Li
  • Danping Shi
  • Yuguang ZhuEmail author
Original Paper



The purpose of our present study was to investigate the expression of cation transport regulator-like protein 1 (CHAC1) in uveal melanoma (UM) tissues and its function in UM progression.


The mRNA expression of CHAC1 in UM tissues and its prognostic value were investigated based on Gene Expression Omnibus database and The Cancer Genome Atlas database. SP6.5 and M23 UM cell lines with depleted CHAC1 were constructed using small interfering RNA. The viability and migration ability of SP6.5 and M23 UM cells were determined by MTT and wound healing assays, respectively. Western blot was conducted to test the influences of CHAC1 depletion on PI3K signaling pathway.


Higher expression of CHAC1 was observed in the UM tissues from patients with liver metastases compared to that from patients without metastases. High CHAC1 expression was correlated with poor prognostic and was an independent predictor for UM patients. Depletion of CHAC1 remarkably inhibited the proliferation and motility of SP6.5 and M23 UM cells. Moreover, the ratios of p-AKT/AKT and p-mTOR/mTOR were reduced notably after silencing CHAC1.


Our results suggested that CHAC1 functioned as a facilitator in UM cell proliferation and migration and possessed the potential to be a predictor as well as a therapeutic target for UM patients.


CHAC1 Uveal melanoma Migration Prognosis PI3K signaling pathway 


Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.


  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A, Ward E, Xu J, Siegael R, Desantis C, Zoy Z (2014) Cancer statistics, 2014. CA Cancer J Clin 62(1):10CrossRefGoogle Scholar
  2. 2.
    Jiang Z, Yu F, Li M (2018) Upregulation of BCL2 19 kD protein-interacting protein 3 (BNIP3) is predictive of unfavorable prognosis in uveal melanoma. Med Sci Monit 24:4711–4717PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Tarlan B, Kıratlı H (2016) Uveal melanoma: current trends in diagnosis and management. Turk J Ophthalmol 46(3):123–137PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Damato B (2012) Progress in the management of patients with uveal melanoma. The 2012 Ashton Lecture. Eye 26(9):1157PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Jager M, Brouwer N, Esmaeli B (2018) The Cancer Genome Atlas Project: an integrated molecular view of uveal melanoma. Ophthalmology 125(8):1139–1142PubMedCrossRefGoogle Scholar
  6. 6.
    Spagnolo F, Caltabiano G, Queirolo P (2012) Uveal melanoma. Cancer Treat Rev 38(5):549–553PubMedCrossRefGoogle Scholar
  7. 7.
    Goebel G, Berger R, Strasak AM, Egle D, Müllerholzner E, Schmidt S, Rainer J, Presul E, Parson W, Lang S (2012) Elevated mRNA expression of CHAC1 splicing variants is associated with poor outcome for breast and ovarian cancer patients. Br J Cancer 106(1):189–198PubMedCrossRefGoogle Scholar
  8. 8.
    Zhang XD, Jiang CC, Wang YF, Wade M, Averykiejda K, Hersey P (2008) The unfolded protein response differentially regulates sensitivities of human melanoma cells to chemotherapeutic drugs. Cancer Res 68:715CrossRefGoogle Scholar
  9. 9.
    Shuda M, Kondoh N, Imazeki N, Tanaka K, Okada T, Mori K, Hada A, Arai M, Wakatsuki T, Matsubara O (2003) Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 38(5):605–614PubMedCrossRefGoogle Scholar
  10. 10.
    Scriven P, Brown N, Pockley A, Wyld L (2007) The unfolded protein response and cancer: a brighter future unfolding? J Mol Med 85(4):331–341PubMedCrossRefGoogle Scholar
  11. 11.
    Jahn B, Arvandi M, Rochau U, Fiegl H, Goebel G, Marth C, Siebert U (2017) Development of a novel prognostic score for breast cancer patients using mRNA expression of CHAC1. J Comp Eff Res 6(7):563–574PubMedCrossRefGoogle Scholar
  12. 12.
    Chen P, Shen W, Shih C, Ho K, Cheng C, Lin C, Lee C, Liu A, Chen K (2017) The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity. Neuropharmacology 116:300–314PubMedCrossRefGoogle Scholar
  13. 13.
    Stelzer Y, Yanuka O, Benvenisty N (2011) Global analysis of parental imprinting in human parthenogenetic induced pluripotent stem cells. Nat Struct Mol Biol 18(6):735–741PubMedCrossRefGoogle Scholar
  14. 14.
    Buchholz M, Braun M, Heidenblut A, Kestler H, Klöppel G, Schmiegel W, Hahn S, Lüttges J, Gress T (2005) Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions. Oncogene 24(44):6626–6636PubMedCrossRefGoogle Scholar
  15. 15.
    Zhang Y, Qiao H, Zhou Y, Hong L, Chen J (2018) Fibrinogen-like-protein 1 promotes the invasion and metastasis of gastric cancer and is associated with poor prognosis. Mol Med Rep 18(2):1465–1472PubMedPubMedCentralGoogle Scholar
  16. 16.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 25(4):402–408CrossRefGoogle Scholar
  17. 17.
    Wang M, Li X, Zhang J, Yang Q, Chen W, Jin W, Huang YR, Yang R, Gao WQ (2017) AHNAK2 is a novel prognostic marker and oncogenic protein for clear cell renal cell carcinoma. Theranostics 7(5):1100–1113PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Xu W, Yang Z, Lu N (2015) A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adhes Migr 9(4):317–324CrossRefGoogle Scholar
  19. 19.
    Mungrue IN, Pagnon J, Kohannim O, Gargalovic PS, Lusis AJ (2009) CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade. J Immunol 182(1):466PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Scriven P, Coulson S, Haines R, Balasubramanian S, Cross S, Wyld L (2009) Activation and clinical significance of the unfolded protein response in breast cancer. Br J Cancer 101(10):1692–1698PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Sun Y, Atmadibrata B, Yu D, Wong M, Liu B, Ho N, Ling D, Tee AE, Wang J, Mungrue IN, Liu PY (2017) Upregulation of LYAR induces neuroblastoma cell proliferation and survival. Cell Death Differ 24(9):1645–1654PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Pompura S, Dominguez-Villar M (2018) The PI3K/AKT signaling pathway in regulatory T-cell development, stability, and function. J Leukoc, BiolCrossRefGoogle Scholar
  23. 23.
    Porta C, Paglino C, Mosca A (2014) Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol 4(4):64PubMedPubMedCentralGoogle Scholar
  24. 24.
    Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT (2017) The PI3K pathway in human disease. Cell 170(4):605PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Li Y, Sun D, Sun W, Yin D (2019) Ras-PI3K-AKT signaling promotes the occurrence and development of uveal melanoma by downregulating H3K56ac expression. J Cell Physiol. PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Ye M, Hu D, Tu L, Zhou X, Lu F, Wen B, Wu W, Lin Y, Zhou Z, Qu J (2008) Involvement of PI3K/Akt signaling pathway in hepatocyte growth factor-induced migration of uveal melanoma cells. Invest Ophthalmol Vis Sci 49(2):497–504PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Yanchen Liu
    • 1
  • Mengyun Li
    • 1
  • Danping Shi
    • 1
  • Yuguang Zhu
    • 2
    Email author
  1. 1.Department of OphthalmologyYidu Central Hospital of WeifangQingzhouPeople’s Republic of China
  2. 2.Department of OphthalmologyThe Affiliated Hospital of Weifang Medical UniversityWeifangPeople’s Republic of China

Personalised recommendations