An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers
Terence K. Lee, … , Ronnie T. Poon, Y. Peng Loh
Terence K. Lee, … , Ronnie T. Poon, Y. Peng Loh
Published February 1, 2011
Citation Information: J Clin Invest. 2011;121(3):880-892. https://doi.org/10.1172/JCI40433.
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Research Article Oncology

An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers

Abstract

Metastasis is a major cause of mortality in cancer patients. However, the mechanisms governing the metastatic process remain elusive, and few accurate biomarkers exist for predicting whether metastasis will occur, something that would be invaluable for guiding therapy. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-ΔN) that drives metastasis. mRNA encoding CPE-ΔN was found to be elevated in human metastatic colon, breast, and hepatocellular carcinoma (HCC) cell lines. In HCC cells, cytosolic CPE-ΔN was translocated to the nucleus and interacted with histone deacetylase 1/2 to upregulate expression of the gene encoding neural precursor cell expressed, developmentally downregulated gene 9 (Nedd9) — which has been shown to promote melanoma metastasis. Nedd9 upregulation resulted in enhanced in vitro proliferation and invasion. Quantification of mRNA encoding CPE-ΔN in HCC patient samples predicted intrahepatic metastasis with high sensitivity and specificity, independent of cancer stage. Similarly, high CPE-ΔN mRNA copy numbers in resected pheochromocytomas/paragangliomas (PHEOs/PGLs), rare neuroendocrine tumors, accurately predicted future metastasis or recurrence. Thus, CPE-ΔN induces tumor metastasis and should be investigated as a potentially powerful biomarker for predicting future metastasis and recurrence in HCC and PHEO/PGL patients.

Authors

Terence K. Lee, Saravana R.K. Murthy, Niamh X. Cawley, Savita Dhanvantari, Stephen M. Hewitt, Hong Lou, Tracy Lau, Stephanie Ma, Thanh Huynh, Robert A. Wesley, Irene O. Ng, Karel Pacak, Ronnie T. Poon, Y. Peng Loh

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Figure 8

Elevated expression and nuclear localization of CPE-ΔN protein in metastatic HCC tumor tissue.

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Elevated expression and nuclear localization of CPE-ΔN protein in metast...
(A) Western blots showing hCPE-ΔN in primary HCC tumors and surrounding tissue from 4 disease-free patients (upper panel) and 4 patients with recurrence (lower panel). (B) The CPE-ΔN band intensity in such blots for n = 80 HCC patients (different from above) were quantified and normalized to the level of actin in the samples. Bar graphs show mean ± SEM (***P < 0.001) of T/N for proteins in disease-free (white) and recurrence (black) groups at 6-month follow-up. (C and E) IHC on primary HCC tumor and adjacent normal hepatic parenchyma (D and F) from patients with (C and D) and without recurrence (E and F). CPE-ΔN staining is predominant in nuclei of cancer cells in the patient with recurrence (C) (arrows). Scale bars: 20 μm (C–F).