As the shadow of cancer continues to expand across the globe, it not only undermines socio-economic structures(Nejatinamini et al. 2021) but also poses a dire threat to human health, a threat compounded by shifting demographics and detrimental lifestyle choices(López-Plaza et al. 2022). This multifaceted disease, notorious for its rampant cellular proliferation and profound physiological disruptions(Pastushenko and Blanpain 2019; Sancar and Van Gelder 2021), stands as a stark reminder of the urgent need for an in-depth exploration into its biological and immunological underpinnings(Chen and Mellman 2017). Despite the steadfast reliance on traditional treatments, the horizon of cancer therapy is being redrawn by the advent of precision medicine(Tsimberidou et al. 2020), groundbreaking strides in targeted therapies(Pérez-Herrero and Fernández-Medarde 2015), and novel immunological responses(Binnewies et al. 2018). Within this realm of endless possibilities, the innovative paradigm of pan-cancer analysis emerges as a beacon of hope, shedding light on shared genetic markers among diverse cancer types and thereby honing treatment strategies. With the ominous predictions of a substantial escalation in global incidences(Sung et al. 2021), the drumbeat for an all-encompassing, collaborative approach in research and healthcare resonates louder than ever.
At the cellular level, the integrity of nuclear-cytoplasmic transport is a linchpin in preserving cellular functions. A skew in this delicate balance contributes significantly to various pathological states, with cancer being the most notorious(Gravina et al. 2014). The karyopherin-β family proteins, including β-importins and exportins, are the sentinels of this transport system, mediating the precise translocation of macromolecules across the nuclear envelope(Wing et al. 2022). However, when disruptions occur, they trigger a cascade of events leading to the abnormal localization and dysregulation of biomolecules critical for cellular differentiation, tumorigenesis, and pharmacological responses in cancerous tissues(Ishizawa et al. 2015; Matsuura 2016; Turner and Sullivan 2008). It is, therefore, imperative to delve into the intricacies of the karyopherin-β family, with a spotlight on exportins, as this exploration could unravel the molecular nuances of cancer pathogenesis and herald a new era of prognostic and therapeutic milestones in oncology.
Central to our investigation is the XPO gene family, encoding seven distinct exportins (XPO1, CSE1L (XPO2), XPO4, XPO5, XPO6, XPO7, and XPOT (XPO3)), each a crucial player in the nuclear-cytoplasmic transport orchestra. They govern the transit of proteins, peptides, and RNA, forming the backbone of cellular functionality. These proteins, though united in purpose, are marked by diversity — manifest in their molecular weights, isoelectric points, sequence identities, and a unifying structural hallmark, the helical HEAT repeats(Nord et al. 2020; Okada et al. 2008; Wing et al. 2022; Ohno 1998). Contemporary research unveils the aberrant expression patterns of specific XPOs across a spectrum of cancers, punctuating their potential as game-changers in prognostic and therapeutic landscapes(Azizian and Li 2020; Azmi et al. 2021; Çağatay and Chook 2018; Mahipal and Malafa 2016). This revelation compels us to meticulously dissect the unique roles and mechanisms employed by each exportin, spotlighting their viability as predictive biomarkers or strategic linchpins in cancer interventions.
The functional tapestry of the XPO family showcases a spectrum of influences across various cancers. For example, XPO1, found to be overexpressed in small-cell lung cancer (SCLC), becomes a harbinger of increased chemosensitivity upon inhibition, thereby bolstering the potency of concurrent chemotherapy regimens(Quintanal-Villalonga et al. 2022). Similarly, in pancreatic cancer, elevated CSE1L expression presents a challenging scenario, signaling a nosedive in prognosis and a potential surge in cell proliferation through the AKT signaling pathway(Zhang et al. 2021). XPOT carves its niche in tumor progression, orchestrating cell cycle processes and ubiquitin-mediated proteolysis, thereby leaving an indelible impact on key cell cycle components in hepatocellular carcinoma (HCC)(Chen et al. 2019; Lin et al. 2019). In a stark contrast, the plot thickens with XPO4(Liang et al. 2011), as a reduction in its expression correlates with not only increased tumor size of HCC but also dismal histopathological outcomes, casting a shadow of bleak prognosis. The narrative takes a curious twist with XPO5 in HCC(Li et al. 2016), where its diminished expression dovetails with tumor-suppressive attributes, a tale recounted through the lens of inhibited cellular proliferation and other oncological signposts. Meanwhile, XPO6, riding the tide of upregulation in prostate cancer, emerges as a potential protagonist in tumor growth and drug resistance, possibly through its sway over the Hippo-YAP1 signaling pathway(Wang et al. 2023). The saga reaches a crescendo with XPO7, whose heightened expression spells doom for prostate cancer outcomes, intensifying malignancy traits in both test tubes and living models. Delving deeper into XPO7 unveils its stranglehold on cell cycle mechanisms and the PI3K-AKT signaling pathways, with a noteworthy liaison with TCF3, underscoring its cardinal role in the march of cancer and spotlighting its potential as a therapeutic bullseye(Lin et al. 2023). These revelations construct a compelling case for personalized therapeutic blueprints, incorporating the nuanced XPO profiles threading through the diverse tapestry of cancers.
To finesse our understanding of the variegated landscape of tumors, our research ventured into uncharted territories with a detailed pan-cancer analysis of XPO family members, spanning 33 cancers from The Cancer Genome Atlas (TCGA)(Weinstein et al. 2013). Our quest transcended the frontiers of gene expression, navigating through the labyrinth of complex relationships entwining XPO genes with survival rates, immune subtypes, stemness, the tumor microenvironment (TME), drug sensitivity, and DNA methylation. Armed with advanced bioinformatics and the treasure trove of public databases, we embarked on a comprehensive comparative odyssey, accentuating the congruencies and disparities in molecular features and clinical impacts of XPOs skirting the contours of cancer types. This analytical crucible not only hones our pre-existing arsenal of knowledge but also catapults these findings to the forefront in the bespoke tailoring of cancer therapies, marking a watershed moment in translational oncology.