The role of delta-like non-canonical Notch ligand 1 (DLK1) in cancer

Abstract

Delta like non-canonical Notch ligand 1 (DLK1) is a cleavable single-pass transmembrane protein and a member of the Notch/Delta/Serrate family. It is paternally expressed and belongs to a group of imprinted genes located on chromosome band 14q32 in humans and 12qF1 in mice. DLK1 is expressed in many human tissues during embryonic development but in adults expression is low and is mostly restricted to (neuro)endocrine tissues and other immature stem/progenitor cells (notably hepatoblasts). However, DLK1 is expressed at a high frequency in many common malignancies (liver, breast, brain, pancreas, colon and lung). More recently, high levels of expression have been identified in endocrine related cancers such as ovarian and adrenocortical carcinoma. There is growing evidence that DLK1 expression in cancer is associated with worse prognosis and that DLK1 may be a marker of cancer stem cells. Although the exact mechanism through which DLK1 functions is not fully understood, it is known to maintain cells in an undifferentiated phenotype and has oncogenic properties. These effects are partly exacted through interaction with the Notch signalling pathway. In this review, we have detailed the functional role of DLK1 within physiology and malignancy and posit a mechanism for how it exacts its oncogenic effects. In describing the expression of DLK1 in cancer and in healthy tissue, we have highlighted the potential for its use both as a biomarker and as a potential therapeutic target.

Pituitary Tumor-Transforming Gene 1/Delta like Non-Canonical Notch Ligand 1 Signaling in Chronic Liver Diseases

“…The human DLK1 has two alternate splicing isoforms: one tethered to the membrane with autocrine effects, and the other cleavable with juxtacrine actions. In contrast, mice DLK1 has six isoforms, with A and B able to produce the larger soluble form and C, C2, D, and D2 being membrane-bound isoforms [50]. All isoforms can yield the smaller soluble product.…”

“…The DLK1 gene encodes for a single pass transmembrane protein of 383 aa. The DLK1 protein consists of a signal peptide (1-23 aa), an extracellular domain of six tandem EGF repeats (24-55, 53-86, 88-125, 127-168, 170-206, 208-245 aa), a juxtamembrane region, a transmembrane domain (304-327 aa), and a short cytoplasmic tail (328-383 aa) (Figure 4) [50]. These EGF repeats are characteristic of proteins related to cell growth and differentiation such as tumor growth factor alpha.…”

“…In contrast, in adults DLK1 expression is generally restricted to neuroendocrine tissues and stem progenitor cells, including the zona glomerulosa of the adrenal gland, pituitary gland, insulin-producing β cells in the pancreas, basal layer of epithelial cells in the prostate, theca interna cells of the ovary, precursor Leydig cells of the testes, epithelial cells of the proximal tubules in the kidney, preadipocytes, and some neurons in the mesencephalon and pons [50].…”

“…DLK1 dysregulation has been documented in several diseases such as metabolic disorders and muscle, lung, and liver regeneration [58,59]. In cancer, DLK1 acts as an oncogene, and elevated expression has been reported in endocrine and non-endocrine malignancies including prostate and ovarian cancers, neuroblastoma, pancreas and colon adenocarcinomas, non-small and small cell lung cancer, HCC, and Wilm's tumor [50].…”

“…Additionally, variable DLK1 protein levels of between 4 and 57% have been reported in patient HCC liver biopsies [50]. Huang et al [154] found elevated expression of the DLK1 gene and protein, measured by real-time PCR and immunohistochemistry, respectively, in human samples of HCC.…”