Abstract
Rhomboid proteins perform a wide range of important functions in a variety of organisms. Recent studies have revealed that rhomboid proteins are involved in human cancer progression; however, the underlying molecular mechanism remains largely unclear. Here we show that RHBDD1, a rhomboid intramembrane serine protease, is highly expressed and closely associated with survival in patients with colorectal cancer. We observe that inactivation of RHBDD1 decreases tumor cell growth. Further studies show that RHBDD1 interacts with proTGFα and induces the ADAM-independent cleavage and secretion of proTGFα. The secreted TGFα further triggers the activation of the EGFR/Raf/MEK/ERK signalling pathway. Finally, the positive correlation of RHBDD1 expression with the EGFR/Raf/MEK/ERK signalling pathway is further corroborated in a murine model of colitis-associated colorectal cancer. These findings provide evidence of a growth-promoting role for RHBDD1 in colorectal cancer and may aid the development of tumor biomarkers or antitumor therapeutics.
Highlights
Rhomboid proteins perform a wide range of important functions in a variety of organisms
To investigate whether the RHBDD1 expression level in tumours is associated with prognosis, we analysed the correlations between RHBDD1 expression and disease-free survival (DFS) and overall survival (OS) in 539 Colorectal cancer (CRC) patients who underwent resection at the Cancer Hospital, Chinese Academy of Medical Sciences, from January 2005 to December 2008
We found that patients with low RHBDD1 expression had better DFS and OS times (N 1⁄4 539, the Kaplan–Meier method with log-rank testing, DFS: P 1⁄4 0.014, OS: P 1⁄4 0.005, Fig. 1d,e)
Summary
Rhomboid proteins perform a wide range of important functions in a variety of organisms. The positive correlation of RHBDD1 expression with the EGFR/Raf/ MEK/ERK signalling pathway is further corroborated in a murine model of colitis-associated colorectal cancer These findings provide evidence of a growth-promoting role for RHBDD1 in colorectal cancer and may aid the development of tumor biomarkers or antitumor therapeutics. In contrast to earlier reports, rhomboid-like 2 (RHBDL2) has recently been found to cleave EGF, facilitate its secretion and trigger the activation of EGFR13 This is the first evidence that mammalian rhomboid proteases are directly involved in EGFR signalling. EGFR hyperactivity is implicated in many cancers[14], and rhomboid proteins, such as RHBDF1 and RHBDD2, are reported to be highly expressed in human cancers[15,16,17] These studies suggest possible links between rhomboids, EGFR signalling and cancer in mammals. Our results support a role for RHBDD1 as a novel prognostic marker or therapeutic target in human CRC
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