Prognostic and functional role of the nuclear export receptor 1 (XPO1) in gastrointestinal cancers: a potential novel target?

Abstract

In the last decades the survival of metastatic gastrointestinal (GI) cancer patients could have been significantly extended due to the introduction of targeted- and immunotherapy. However, only the minority of patients will experience long-lasting survival. Hence, novel therapeutics are clearly necessary for GI cancer patients. Molecular high-throughput profiling techniques have revealed potential novel targetable molecular alterations, emphasizing the necessity for tailored therapeutic approaches. Nuclear export proteins, particularly Exportin-1 (XPO1), have emerged as promising targets in cancer therapy due to their crucial role in cellular homeostasis and regulation of key cellular functions. Dysregulation of XPO1-mediated nuclear export leads to the functional loss of tumor suppressors and pro-apoptotic factors, facilitating cancer progression. Selinexor, a XPO1 inhibitor, has shown promising activity in preclinical and clinical studies, particularly in hematological malignancies. However, its efficacy in GI cancers remains underexplored. This review aims to elucidate the functional and pathophysiological role of XPO1 in GI cancers. Despite the potential of XPO1 inhibitors in suppressing cell proliferation and inducing apoptosis, comprehensive molecular landscape data and validation of selective inhibitors in GI cancers are lacking. Targeting XPO1 presents a significant therapeutic potential for the treatment of GI cancer patients. Further research is necessary to fully elucidate the molecular landscape according to XPO1 expression in GI tumors and to validate the efficacy of selective XPO1 inhibitors. These efforts are expected to contribute to the development of more effective and personalized therapeutic strategies for GI cancer patients.

Keywords: Cancer therapy; Gastrointestinal cancers; Nuclear export proteins; SINE; Selinexor; XPO1; XPO1 inhibitor.

Fig. 1

a Domains of XPO1 protein: Importin-beta N-terminal domain, Exportin-1-like protein, XPO1 C terminal domain. b Ring shaped structure of XPO1, domains and Cys528 residue. (orange: Importin-beta N-terminal domain, yellow: Exportin-1-like protein, blue: C terminal domain)

Fig. 2

Transport mechanism of XPO1-mediated nuclear export of protein and RNA cargoes Left: Schematic representation of the transport of RNA cargoes by XPO1. Right: Schematic representation of the transport of protein cargoes by XPO1. In both cases, XPO1 forms a complex with RanGTP and the protein cargoes (or RNA cargoes and adapter protein), which is transported through the NPC. The complex then disassembles in the cytoplasm, converting RanGTP to RanGDP and releasing the XPO1 cargoes into the cytoplasm. XPO1 then migrates back into the nucleus and repeats the whole process. Created with BioRender.com

Fig. 3

a XPO1 mRNA expression in gastrointestinal cancer tissues compared to non-tumor tissues. b Selective inhibitor of nuclear export (SINE) mechanism. SINE compounds selectively inhibit XPO1, disrupting the nuclear export of cargo proteins and RNAs and thus preventing their transport to the cytoplasm. (abbreviations: ESCA: Esophageal carcinoma, STAD: Stomach adenocarcinoma, COAD: Colon adenocarcinoma, LIHC: Liver hepatocellular carcinoma, CHOL: Cholangiocarcinoma, PAAD: Pancreatic adenocarcinoma) Created with BioRender.com

Fig. 4

Data (mRNA & clinical data) was acquired from TCGA and cBioportal using the R packages TCGA biolinks and cbioportalR, respectively. Counts (mRNA) were normalized using the within & between lane normalization from the EDASeq package. Ideal cut-offs for XPO1 high and low tumors were determined iteratively using the survival package to choose the cut-off with the largest difference in survival. P values reported concern the difference in survival and are from a logrank-test. Differential gene expression was analyzed using the limma package – plots show the log2-fold change between groups on the x-axis and the log10(p-value) on the y-axis. The large blue dot represents XPO1. The results shown here are in whole based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. (Abbreviations: TCGA: The Cancer Genome Atlas, COAD: colon adenocarcinoma, ESCA: esophageal carcinoma, STAD: stomach adenocarcinoma, LIHC: liver hepatocellular carcinoma, PAAD: pancreatic adenocarcinoma, CHOL: cholangiocarcinoma, LogFC: log2-fold change)