DCLK1 is correlated with MET and ERK5 expression, and associated with prognosis in malignant pleural mesothelioma

Our plain-English summary of DCLK1 is correlated with MET and ERK5 expression, and associated with prognosis in malignant pleural mesothelioma, by H. Wang, Y.Y. Dai, W.Q. Zhang, et al (International Journal of Oncology, 2017).

The study

• Authors: H. Wang, Y.Y. Dai, W.Q. Zhang, P.C. Hsu, Y.L. Yang, Y.C. Wang, G. Chan, A. Au, Z.D. Xu, S.J. Jiang, W. Wang, D.M. Jablons, L. You
• Journal: International Journal of Oncology
• Published: 2017;51(1):91-103
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer for which more effective treatments are needed. In this study, strong to moderate staining of MET and ERK5 was detected in 67.1 and 48% of the analyzed 73 human mesothelioma tumors, and significant correlation of MET and ERK5 expression was identified (P<0.05). We evaluated the doublecortin-like kinase 1 (DCLK1) expression in human mesothelioma tumors. Our results showed that 50.7% of the immunohistochemistry analyzed human mesothelioma tumors have strong to moderate staining of DCLK1, and its expression is significantly correlated with MET or ERK5 expression (P<0.05). Also, the upregulation of DCLK1 is correlated with poor prognosis in MPM patients (P=0.0235). To investigate whether DCLK1 is downstream of MET/ERK5 signaling in human mesothelioma, the effect of DCLK1 expression was analyzed after treatments with either the MET inhibitor XL184 or the ERK5 inhibitor XMD8-92 in human mesothelioma cell lines. Our results showed that the MET inhibitor XL184 reduced the expression of phospho‑ERK5 and DCLK1 expression in human mesothelioma cell lines. In addition, the ERK5 inhibitor XMD8-92 reduced the expression of phospho-ERK5 and DCLK1 expression in human mesothelioma cell lines. Furthermore, XML184 and XMD8-92 treatment impaired invasion and tumor sphere formation ability of H290 mesothelioma cells. These results suggest that DCLK1 is regulated by MET/ERK5 signaling in human mesothelioma, and the MET/ERK5/DCLK1 signaling cascade could be further developed into a promising therapeutic target against mesothelioma.

In plain English

This laboratory study looked at three proteins, MET, ERK5 and DCLK1, in malignant pleural mesothelioma. The authors stained tumor samples from 73 patients operated on at the University of California, San Francisco between 1997 and 2008, plus normal pleural tissue from 8 of them. They also treated mesothelioma cell lines with two inhibitor drugs, XL184 (for MET) and XMD8-92 (for ERK5). Asbestos exposure was not studied. Moderate to strong staining was found in 67.1% of tumors for MET, 48% for ERK5 and 50.7% for DCLK1. The levels of the three proteins were significantly associated with one another. Among 45 patients with complete records, those with high DCLK1 staining had significantly shorter survival (P=0.0235). In two cell lines, both drugs lowered DCLK1 levels. They also reduced invasion and tumor-sphere formation in the H290 cell line. The authors concluded that DCLK1 may predict prognosis and appears to be regulated by MET and ERK5 signaling. They noted that XL184 also acts on targets other than MET.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: immunohistochemistry staining of human tumor tissue, survival analysis, and cell-line experiments with inhibitor drugs
• Who was studied: Tumor samples from 73 patients with malignant pleural mesothelioma who had surgery at the University of California, San Francisco Medical Center from July 1997 to December 2008. Normal pleural tissue was available from 8 of these patients, and complete clinical information from 45. The study also used six mesothelioma cell lines and one normal mesothelial cell line (LP9).
• Exposure: Asbestos exposure was not studied. In the cell experiments, cells were treated with the MET inhibitor XL184 and the ERK5 inhibitor XMD8-92.
• Main results:
  • MET: moderate to strong staining in 67.1% of the 73 tumor samples, compared with 12.5% of the 8 normal pleural tissues
  • ERK5: moderate to strong staining in 48% of tumor samples and in none of the normal pleural tissues
  • DCLK1: moderate to strong staining in 50.7% of tumor samples and in none of the normal pleural tissues
  • In the tumor samples, levels of MET, ERK5 and DCLK1 were significantly associated with one another (P less than 0.05, chi-square test)
  • Among the 45 patients analyzed for survival, those with high DCLK1 staining (score 2 to 3) had significantly shorter survival than those with low staining (score 0 to 1), P=0.0235
  • DCLK1 level was not significantly related to age, gender, smoking status or TNM stage
  • In H290 and H513 mesothelioma cells, both XL184 and XMD8-92 lowered phospho-MET, phospho-ERK5 and DCLK1 protein levels compared with control-treated cells
  • Both drugs significantly reduced invasion by H290 cells compared with controls. XMD8-92 did not affect invasion by H2052 cells.
  • Tumor-sphere formation by H290 cells fell significantly, in a dose-dependent way, after either drug
• The authors' conclusion: The authors concluded that DCLK1 may serve as a predictor of prognosis in malignant pleural mesothelioma patients, and that their results suggest DCLK1 is regulated by MET/ERK5 signaling in human mesothelioma.
• Limitations the authors state:
  • The authors could not rule out that XL184's effects came partly from blocking other targets, such as VEGFR2 and RET
  • Complete clinical information was available for only 45 of the 73 patients

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Prognosis, Pleural Mesothelioma, Mesothelioma, Immunohistochemistry.

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