Colorectal cancer (CRC) is one of the most common cancer types and the second leading cause of cancer-related death worldwide (Dekker et al., 2019, Siegel et al., 2020). Although significant improvements have been made in the management of CRC, metastasis remains common, contributing to a poor prognosis; approximately 25% of patients with CRC present metastatic cancer at diagnosis (Lin et al., 2021) Understanding the genetic alterations involved in CRC progression and metastasis may help identify novel CRC biomarkers and provide potential avenues for targeted therapies.

Autophagy, a conserved lysosomal degradation process, plays a critical role in metabolic stress, starvation adaptation, neurodegenerative diseases, inflammatory diseases, and cancer (Choi et al., 2013, Mizushima and Levine, 2020). However, the regulatory role of autophagy in CRC development and metastasis remains unknown. G-protein signaling modulator 1 (GPSM1), an activator of G-protein signaling 3 (AGS3), was first identified as a receptor-independent activator of heterotrimeric G-proteins in Saccharomyces cerevisiae (Cismowski et al., 1999). GPSM1 contains four C-terminal G-protein regulatory (GPR) motifs and seven N-terminal tetratricopeptide repeats (TPRs) (Adhikari and Sprang, 2003). Each GPR motif functions as a guanine nucleotide dissociation inhibitor that stabilizes the Gα subunit during GDP-binding, while TPRs influence the intramolecular dynamics and subcellular distribution of GPSM1 (Bernard et al., 2001, De Vries et al., 2000, Pattingre et al., 2003). Previous studies have shown that GPSM1 is expressed in a tissue-specific manner and participates in multiple physiological and pathophysiological processes such as metabolism, cardiovascular regulation, autophagy, polycystic kidney disease, neuronal plasticity, and addiction (Blumer et al., 2008, Kelley and Schiltz, 2004, Nadella et al., 2010). Furthermore, GPSM1 is associated with cell division, membrane protein trafficking, leukocyte chemotaxis, and calcium mobilization (Branham-O’Connor et al., 2014, Gotta et al., 2003, Groves et al., 2007, Sanada and Tsai, 2005). Recently, GPSM1 overexpression was detected in several cancer types and was suggested to be a critical factor in regulating cell proliferation, migration, invasion, and apoptosis by activating the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling pathway (Adekoya et al., 2019, Shao et al., 2014, Shi et al., 2015). However, functional experiments deciphering the dynamics of the regulatory relationship between GPSM1 and autophagy and the clinical significance of GPSM1 in CRC metastasis have not yet been reported.

In the present study, we investigated the effects of the expression of GPSM1 on the clinicopathological characteristics and overall survival of Chinese Han patients with CRC. In addition, we evaluated the autophagy-related molecular mechanisms of GPSM1 in CRC using in vivo and in vitro models. These results may provide new insights into the biological function of GPSM1 in CRC and suggest new therapeutic targets.