Prognostic and diagnostic value of REG4 serum and tissue expression in pancreatic ductal adenocarcinoma

Introduction

With over 40,000 annual deaths in the United States, and with a devastating overall 5-year survival under 5%,¹ pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Radical surgical resection with or without chemotherapy is the only treatment for cure but is possible in only 20% of patients.² Despite extensive research on potential biomarkers, since CA19-9, none has deserved a role in clinical praxis. Identification of new biomarkers is imperative to predict PDAC patient outcome more precisely and to advance our knowledge of the molecular mechanisms behind this disease.^3,4

REG4 in cancer

The regenerating islet-derived (REG) proteins are a group of small secretory proteins involved in regulation of cell regeneration and proliferation.^5,6 Among the four REG families (I–IV), REG4 is the most recently discovered member. In 2001, it was identified and isolated from a complementary DNA (cDNA) library of ulcerative colitis tissue.⁷ REG4 is physiologically expressed in the colon and small intestine, where it is highly expressed in enteroendocrine cells,^8,9 but not in the pancreatic islets.

Upregulation of REG4 expression occurs in inflammatory bowel diseases (IBD),^7,8 but its expression is also increased in many gastrointestinal malignancies such as colorectal,¹⁰ gastric,¹¹ or pancreatic cancer.¹² Evidence exists that REG4 is expressed more strongly in colorectal tumors and normal small intestine than in normal colorectal tissue.¹³ Zhang et al.¹⁴ proposed that overexpression of REG4 may be an early event in colorectal carcinogenesis, showing that REG4 expression was higher in dysplastic adenomas than in normal colorectal mucosa. REG4 is expected to play a role also in gastric carcinogenesis.¹⁵

REG4 can serve as a diagnostic serum marker in colorectal cancer (CRC) with liver metastasis, but it does not detect early tumor stages.¹⁰ Serum levels of REG4 are significantly higher in patients with gastric cancer than in healthy individuals at a sensitivity of 36%–73%, higher than that of CEA or CA19-9.^11,16 High serum REG4 level can differentiate mucinous ovarian cancer from other ovarian cancer subtypes and may prove useful in follow-up of this disease.¹⁷

REG4 in pancreatic cancer

Several reports show REG4 expression in pancreatic cancer cells to be increased above the level in normal pancreatic cells, and REG4 to promote invasiveness...