RHOA at the intersection of inflammation-driven and sporadic colorectal cancer

In the last decades, colorectal cancer (CRC) has emerged as a global problem, representing approximately 10% of all malignant tumors and the second leading cause of cancer-related death. Colitis-associated cancer (CAC) arises from chronic unresolved inflammation and is typically characterised by poor prognosis. Among key cellular regulators, the small GTPase RHOA controls cytoskeleton dynamics in various cell types and, thereby, key biological processes. Although it has been linked to various diseases, the role of RHOA in cancer remains controversial. RHOA has been proposed as a biomarker in cancer including CRC, but recent evidence shows that RHOA inactivation increases Wnt signalling and tumour risk in the murine intestinal epithelium. This review summarises the mechanisms of RHOA function and regulation and analyses the oncogenic pathways in which it is involved, with a focus on sporadic CRC and CAC. We discuss whether the RHOA pathway serves the same function in the two types of intestinal cancer and how the inflammatory context can modulate RHOA outcome following activation or inhibition, which still remains an open question. Finally, we address opportunities for therapeutic targeting of RHOA and related proteins. The understanding of the function of RHOA specifically in CRC may help identify limitations that might have hampered the development of novel targets for optimized treatment and/or diagnostic strategies.