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Overexpressed CA12 has prognostic value in pancreatic cancer and promotes tumor cell apoptosis via NF-κB signaling

  • Original Article – Clinical Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Introduction

Pancreatic adenocarcinoma (PAAD) is among the deadliest forms of cancer globally. Carbonic anhydrase 12 (CA12) is known to play central roles in regulating many cancers, but its function in the context of PAAD is rarely discussed. This study was, therefore, designed to assess the expression of CA12 in PAAD and to explore its underlying mechanistic role in this cancer type.

Methods

Immunohistochemical staining was used to measure CA12 expression in PAAD samples. The functionality of pancreatic cancer cells expressing varying levels of CA12 was assessed through wound healing, Transwell, and CCK-8 assays. In addition, flow cytometry was used to measure apoptosis and cell cycle progression in these same cells, while Western blotting was used to analyze the expression of proteins associated with the NF-κB signaling pathway.

Results

PAAD tissue samples exhibited significant CA12 downregulation (P < 0.001), and lower CA12 expression was, in turn, associated with poorer overall survival (P < 0.001). CA12 overexpression significantly impaired the proliferation of PAAD cell lines, instead inducing their apoptotic death and G0/G1 phase cell cycle arrest (P < 0.05). We additionally found that CA12 may exert its tumor suppressive roles via modulating the NF-κB signaling pathway.

Conclusion

These results indicate that CA12 functions as a tumor suppressor in PAAD and may thus be a novel therapeutic target that can be used to guide PAAD patient treatment.

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References

  • Alfarouk KO (2016) Tumor metabolism, cancer cell transporters, and microenvironmental resistance. J Enzyme Inhib Med Chem 31:859–866

    Article  CAS  Google Scholar 

  • Asgharzadeh MR, Barar J, Pourseif MM et al (2017) Molecular machineries of pH dysregulation in tumor microenvironment: potential targets for cancer therapy. Bioimpacts 7:115–133

    Article  CAS  Google Scholar 

  • Baniak N, Flood TA, Buchanan M et al (2020) Carbonic anhydrase IX (CA9) expression in multiple renal epithelial tumour subtypes. Histopathology 77:659–666

    Article  Google Scholar 

  • Becker HM (2020) Carbonic anhydrase IX and acid transport in cancer. Br J Cancer 122:157–167

    Article  CAS  Google Scholar 

  • Bharti AC, Donato N, Singh S et al (2003) Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 101:1053–1062

    Article  CAS  Google Scholar 

  • Cheng S, Zhang X, Huang N et al (2016) Down-regulation of S100A9 inhibits osteosarcoma cell growth through inactivating MAPK and NF-κB signaling pathways. BMC Cancer 16:253

    Article  Google Scholar 

  • Chun YS, Pawlik TM, Vauthey JN (2018) 8th edition of the AJCC cancer staging manual: pancreas and hepatobiliary cancers. Ann Surg Oncol 25:845–847

    Article  Google Scholar 

  • Gillen S, Schuster T, Meyer Zum Büschenfelde C et al (2010) Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med 7:e1000267

    Article  Google Scholar 

  • Holcomb B, Yip-Schneider M, Schmidt CM (2008) The role of nuclear factor kappaB in pancreatic cancer and the clinical applications of targeted therapy. Pancreas 36:225–235

    Article  CAS  Google Scholar 

  • Hsieh MJ, Chen KS, Chiou HL et al (2010) Carbonic anhydrase XII promotes invasion and migration ability of MDA-MB-231 breast cancer cells through the p38 MAPK signaling pathway. Eur J Cell Biol 89:598–606

    Article  CAS  Google Scholar 

  • Ilie MI, Hofman V, Ortholan C et al (2011) Overexpression of carbonic anhydrase XII in tissues from resectable non-small cell lung cancers is a biomarker of good prognosis. Int J Cancer 128:1614–1623

    Article  CAS  Google Scholar 

  • Ivanov S, Liao SY, Ivanova A et al (2001) Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158:905–919

    Article  CAS  Google Scholar 

  • Juhász M, Chen J, Lendeckel U et al (2003) Expression of carbonic anhydrase IX in human pancreatic cancer. Aliment Pharmacol Ther 18:837–846

    Article  Google Scholar 

  • Justus CR, Dong L, Yang LV (2013) Acidic tumor microenvironment and pH-sensing G protein-coupled receptors. Front Physiol 4:354

    Article  Google Scholar 

  • Karin M (2009) NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol 1:a000141

    Article  Google Scholar 

  • Kivela AJ, Parkkila S, Saarnio J et al (2005) Expression of von Hippel-Lindau tumor suppressor and tumor-associated carbonic anhydrases IX and XII in normal and neoplastic colorectal mucosa. World J Gastroenterol 11:2616–2625

    Article  CAS  Google Scholar 

  • Kunnumakkara AB, Guha S, Krishnan S et al (2007) Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res 67:3853–3861

    Article  CAS  Google Scholar 

  • Ledoux AC, Perkins ND (2014) NF-κB and the cell cycle. Biochem Soc Trans 42:76–81

    Article  CAS  Google Scholar 

  • Lee S, Shin HJ, Han IO et al (2007) Tumor carbonic anhydrase 9 expression is associated with the presence of lymph node metastases in uterine cervical cancer. Cancer Sci 98:329–333

    Article  CAS  Google Scholar 

  • Li Y, Dong M, Sheng W et al (2016) Roles of carbonic anhydrase IX in development of pancreatic cancer. Pathol Oncol Res 22:277–286

    Article  CAS  Google Scholar 

  • Li Y, Lei B, Zou J et al (2019) High expression of carbonic anhydrase 12 (CA12) is associated with good prognosis in breast cancer. Neoplasma 66:420–426

    Article  Google Scholar 

  • Liu R, Lv QL, Yu J et al (2015) Correlating transcriptional networks with pathological complete response following neoadjuvant chemotherapy for breast cancer. Breast Cancer Res Treat 151:607–618

    Article  CAS  Google Scholar 

  • Parkkila S, Parkkila AK, Saarnio J et al (2000) Expression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumors. J Histochem Cytochem 48:1601–1608

    Article  CAS  Google Scholar 

  • Potter CP, Harris AL (2003) Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancer. Br J Cancer 89:2–7

    Article  CAS  Google Scholar 

  • Prabhu L, Mundade R, Korc M et al (2014) Critical role of NF-κB in pancreatic cancer. Oncotarget 5:10969–10975

    Article  Google Scholar 

  • Rahib L, Smith BD, Aizenberg R et al (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921

    Article  CAS  Google Scholar 

  • Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8:138–140

    CAS  PubMed  Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69:7–34

    Article  Google Scholar 

  • Supuran CT (2008) Carbonic anhydrases—an overview. Curr Pharm Des 14:603–614

    Article  CAS  Google Scholar 

  • Tang Z, Li C, Kang B et al (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45:W98-w102

    Article  CAS  Google Scholar 

  • Tashian RE (1989) The carbonic anhydrases: widening perspectives on their evolution, expression and function. BioEssays 10:186–192

    Article  CAS  Google Scholar 

  • Thiry A, Dogné JM, Masereel B et al (2006) Targeting tumor-associated carbonic anhydrase IX in cancer therapy. Trends Pharmacol Sci 27:566–573

    Article  CAS  Google Scholar 

  • Türeci O, Sahin U, Vollmar E et al (1998) Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers. Proc Natl Acad Sci USA 95:7608–7613

    Article  Google Scholar 

  • Wang W, Abbruzzese JL, Evans DB et al (1999) The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 5:119–127

    CAS  PubMed  Google Scholar 

  • Wang G, Cheng Z, Liu F et al (2015) CREB is a key negative regulator of carbonic anhydrase IX (CA9) in gastric cancer. Cell Signal 27:1369–1379

    Article  CAS  Google Scholar 

  • Watson PH, Chia SK, Wykoff CC et al (2003) Carbonic anhydrase XII is a marker of good prognosis in invasive breast carcinoma. Br J Cancer 88:1065–1070

    Article  CAS  Google Scholar 

  • Wei S, Yun X, Ruan X et al (2019) Identification of potential pathogenic candidates or diagnostic biomarkers in papillary thyroid carcinoma using expression and methylation profiles. Oncol Lett 18:6670–6678

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wykoff CC, Beasley N, Watson PH et al (2001) Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. Am J Pathol 158:1011–1019

    Article  CAS  Google Scholar 

  • Yang L, Yang Z, Li D et al (2018) Overexpression of FZD1 and CAIX are associated with invasion, metastasis, and poor-prognosis of the pancreatic ductal adenocarcinoma. Pathol Oncol Res 24:899–906

    Article  CAS  Google Scholar 

  • Yoo CW, Nam BH, Kim JY et al (2010) Carbonic anhydrase XII expression is associated with histologic grade of cervical cancer and superior radiotherapy outcome. Radiat Oncol 5:101

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the National Natural Science Foundation of China (No. 81772516).

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Author notes

  1. Yan Du and Zechang Xin have contributed equally to this work.

Authors and Affiliations

  1. Dalian Medical University, Dalian, 116044, Liaoning, People’s Republic of China

    Yan Du & Zechang Xin

  2. Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People’s Hospital, Nantong Western Road, Guangling Qu, Yangzhou, Jiangsu, 225001, People’s Republic of China

    Tongtai Liu, Peng Xu & Jie Yao

  3. Medical College of Yangzhou University, Yangzhou, Jiangsu, 225001, People’s Republic of China

    Feiyu Mao & Jie Yao

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  1. Yan Du
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  2. Zechang Xin
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  4. Peng Xu
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  5. Feiyu Mao
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Correspondence to Jie Yao.

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Du, Y., Xin, Z., Liu, T. et al. Overexpressed CA12 has prognostic value in pancreatic cancer and promotes tumor cell apoptosis via NF-κB signaling. J Cancer Res Clin Oncol 147, 1557–1564 (2021). https://doi.org/10.1007/s00432-020-03447-9

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  • DOI: https://doi.org/10.1007/s00432-020-03447-9

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