Rhomboid domain containing 1 promotes colorectal cancer growth through activation of the EGFR signalling pathway

Wei Song  ¹ , Wenjie Liu  ¹ , Hong Zhao  ² , Shangze Li  ³ , Xin Guan  ¹ , Jianming Ying  ⁴ , Yefan Zhang  ² , Fei Miao  ¹ , Mengmeng Zhang  ¹ , Xiaoxia Ren  ¹ , Xiaolu Li  ¹ , Fan Wu  ¹ , Yuechao Zhao  ¹ , Yuanyuan Tian  ¹ , Wenming Wu  ⁵ , Jun Fu  ¹ , Junbo Liang  ¹ , Wei Wu  ¹ , Changzheng Liu  ¹ , Jia Yu  ¹ , Shudong Zong  ⁶ , Shiying Miao  ¹ , Xiaodong Zhang  ³ , Linfang Wang  ¹

• ¹ Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China.
• ² Department of Abdominal Surgical Oncology, Cancer Hospital &Institute, Chinese Academy of Medical Sciences, Beijing 100021, China.
• ³ College of Life Sciences, Wuhan University, Wuhan 430072, China.
• ⁴ Department of Pathology, Cancer Hospital &Institute, Chinese Academy of Medical Sciences, Beijing 100021, China.
• ⁵ Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
• ⁶ National Research Institute for Family Planning, WHO Collaboration Center of Human Reproduction, Beijing 100081, China.

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.