Association of XPO1 Overexpression with NF-κB and Ki67 in Colorectal Cancer

Abstract

also known as chromosome region maintenance 1 (CRM1) protein, is involved in the homeostatic of nucleocytoplasmic transport of over 200 known cargos, most of them are tumor suppressor and cell cycle regulatory proteins such as p53, pRb, FOXOs, BRCA1/2 and inhibitor of NF-κB (Kau et al., 2004; Abstract Objectives: Exportin 1(XPO1), a nuclear exporter protein, has been gaining recognition in cancer progression and treatment. This study aimed to evaluate the association between the overexpression of XPO1 with NF-κB, Ki67 and clinicopathological characteristics in colorectal cancer (CRC) tissue samples and to explore the anti-proliferative effect of KPT-330, as XPO1 inhibitor, in colorectal cancer cell line. Methods: Forty CRC tissue samples were analyzed by immunostaining for the expressions of XPO1, NF-κB and Ki67 and then the anti-proliferative effect of the KPT-330 was also evaluated in HT29 colorectal cancer cell line. Results: XPO1 overexpression was observed in 52.5% of CRC and significantly apparent with strong intensity in tumor cells compared to the normal adjacent epithelium (P<0.001).Regarding to the histopathological characteristics, the XPO1 overexpression significantly associated with advanced tumor stages (P=0.049) and has great tendency towards moderate/poorly differentiated tumors. Although the XPO1 overexpression was strongly associated with high Ki67 expression (P=0.001), only Ki67 expression showed significant association with tumor size (P=0.012). No significant association was detected between the XPO1 overexpression and NF-κB, while the NF-κB positive expression was significantly associated with lymph node metastasis and Ki67 expression at P=0.027 and P= 0.007, respectively. The in vitro experiments showed a great impact of KPT-330, as XPO1 inhibitor, to inhibit cancer growth in dose and time dependent manner and significantly diminished the colony formation (P<0.001) of HT29 cells-associated with the expression of Ki67 (P<0.001). Conclusion: XPO1 overexpression and NF-κB expression may serve as potential biomarker associated with CRC pathogenesis and proliferation, while the KPT-330 is effectively inhibited-colon cancer growth in vitro. Further studies considering the prognostication role of XPO1 overexpression in CRC are required.

XPO1-dependent nuclear export as a target for cancer therapy

“…XPO1/CRM1 as an oncogenic driver and therapeutic target in cancer XPO1 overexpression is a common feature among many human cancer types, including pancreatic, ovarian, glioma, lung, gastric, prostate, and colorectal cancers, and is associated with poor prognosis [34][35][36][37][38][39][40]. While amplified copy number may explain the XPO1 overexpression in some leukemia and lymphoma subtypes [41], for the majority of human cancers, the mechanism of XPO1 overexpression remains unknown.…”

Decoding nonspecific interactions between human nuclear transport proteins: A computational study

“…It transports approximately 220 proteins ( Fu et al, 2013 ). Like other transport proteins, it is also involved in the various cancers and plays a critical role (Aladhraei et al, 2019; Camus et al, 2017; David et al, 2019; J. Kim et al, 2016 ).…”

XPO1 inhibition with selinexor synergizes with proteasome inhibition in neuroblastoma by targeting nuclear export of IkB

“…These results suggests that drug sensitivity in patients would be independent of XPO1 expression even though expression can serve as a prognostic biomarker. Retrospective studies of XPO1 expression show how critical XPO1 is to the oncogenic process but with the lack of knowledge on how overexpression occurs, it is the cargo proteins and pathways thereof that remain the most promising for a therapeutic marker of response [ 43 , 44 ].…”