Abstract
ARTEMIN (ARTN), one of the glial-cell derived neurotrophic factor family of ligands, has been reported to be associated with a number of human malignancies. In this study, the enhanced expression of ARTN in colorectal carcinoma (CRC) was observed; the expression of ARTN positively correlated with lymph node metastases and advanced tumor stages and predicted poor prognosis. Forced expression of ARTN in CRC cells enhanced oncogenic behavior, mesenchymal phenotype, stem cell-like properties and tumor growth and metastasis in a xenograft model. These functions were conversely inhibited by depletion of endogenous ARTN. Forced expression of ARTN reduced the sensitivity of CRC cells to 5-FU treatment; and 5-FU resistant CRC cells harbored enhanced expression of ARTN. The oncogenic functions of ARTN were demonstrated to be mediated by p44/42 MAP kinase dependent expression of CDH2 (CADHERIN 2, also known as N-CADHERIN). Inhibition of p44/42 MAP kinase activity or siRNA mediated depletion of endogenous CDH2 reduced the enhanced oncogenicity and chemoresistance consequent to forced expression of ARTN induced cell functions; and forced expression of CDH2 rescued the reduced mesenchymal properties and resistance to 5-FU after ARTN depletion. In conclusion, ARTN may be of prognostic and theranostic utility in CRC.
Highlights
Colorectal carcinoma (CRC) is the fourth most diagnosed cancer accounting for 8.5% of cancer related death globally [1]
We demonstrated that the pharmacological inhibition of p44/42 Mitogen-Activated Protein Kinase (MAPK) phosphorylation using MEK inhibitor, U0126, markedly reduced the protein levels of Protein Cadherin 2 (CDH2) in DLD1 cells, without affecting the endogenous protein levels of ARTN (Figure 7F)
Given that it has recently been described that ARTN is produced by splenic Ter cells, and secreted to serum to promote hepatocellular carcinoma progression [42], examination of tumor ARTN expression will potentially underestimate the full contribution of ARTN to relapse and survival
Summary
Colorectal carcinoma (CRC) is the fourth most diagnosed cancer accounting for 8.5% of cancer related death globally [1]. Metastasis, especially hepatic metastases, remains the predominant cause of CRC-related death in patients [2, 3]. CRC patients with distant metastases exhibit dismal 5-year survival rates of 14% [4]. Radiation, chemotherapy and targeted therapy, or combinations of these therapies are currently available treatment options for CRC patients. The introduction of chemotherapy dramatically improved the median survival of metastatic CRC (mCRC) patients when 5fluorouracil (5-FU, an analog of fluoropyrimidine) was first applied in the treatment of mCRC [5]. Targeted therapies were later utilized in treatment of CRC with or without chemotherapy. There are currently nine FDAapproved targeted agents for CRC of which 2 are anti-EGFR, 4 are anti-VEGF/VEGFR and 3 are immune checkpoint inhibitors [7]. The development of novel validated oncogenic targets for prognosis and therapy is of urgent importance to ameliorate CRC treatment outcomes
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