Exportin 1 (XPO1) inhibition leads to restoration of tumor suppressor miR-145 and consequent suppression of pancreatic cancer cell proliferation and migration

Azmi, Asfar S.; Li, Yiwei; Muqbil, Irfana; Aboukameel, Amro; Senapedis, William; Baloglu, Erkan; Landesman, Yosef; Shacham, Sharon; Kauffman, Michael; Philip, Philip A.; Mohammad, Ramzi M.

doi:10.18632/oncotarget.19285

Cited by 45 publications

(39 citation statements)

References 56 publications

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“…The above results fall in-line with the published data about the KPT-330 ability to sequester the cargoes such as tumor suppressor proteins within the nucleus and leads to cell cycle arrest and proliferation inhibition. The anti-proliferative effect of XPO1 inhibitors were reported in different types of cancer cell lines such as pancreatic cells (Azmi et al, 2017), liver cells (Zheng et al, 2014), prostate cells (Gravina et al, 2015), and gastric cells (Subhash et al, 2018) as well as in colon cancer cell lines (Draetta et al, 2011;Niu et al, 2015). In conclusion, an apparent of XPO1 overexpression in CRC tumor cells compared to the adjacent normal epithelium as well as the association of XPO1 overexpression with advance tumor stages, tumor differentiation and high Ki67 expression may reflect its potential involvement in CRC pathogenesis which can be inhibited by KTP-330.…”

Section: Overexpressionmentioning

confidence: 99%

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

Al-Adhraei

Al‐Thobhani

Poungvarin

et al. 2019

Asian Pac J Cancer Prev

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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.

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Section: Overexpressionmentioning

confidence: 99%

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

Al-Adhraei

Al‐Thobhani

Poungvarin

et al. 2019

Asian Pac J Cancer Prev

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“…Elevated nuclear localization of PAK4 influences breast-to-bone metastasis by targeting the metastasis suppressor, LIFR (51). Targeting of PAK4 via miRNAs, including miR-199a/b-3p (30,39,40,44), miR-485 (41), miR-342 (52), miR-145 (53,54), miR-24-1-5p (55), miR-224 (56), miR-126 (44), and miR-433 (57) suppresses cancer cell proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

Therapeutically actionable PAK4 is amplified, overexpressed and involved in bladder cancer progression

Chandrashekar

Chakravarthi

Robinson

et al. 2019

Preprint

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Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Disease incidence and survival rates vary based on aggressiveness and treatment options. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. For a minority (~20%) of patients, T-cell checkpoint inhibitors provide durable benefits following prior platinum therapy. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting heterogeneity in these tumors and pointing to the importance of molecular characterization of MIBCs to provide effective treatment. We have performed multi-omic profiling of the kinome to identify therapeutic targets that are overexpressed in a subset of BLCAs. Our analyses revealed amplification and overexpression of P21 (RAC1) activated kinase 4 (PAK4) in a subset of BLCAs. For these tumors, multiplex kinase assay profiling identified corresponding PAK4 target substrates. By performing experiments using cultured bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, our studies showed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, Protein Tyrosine Kinase 6 (PTK6), upon treatment with a PAK4 inhibitor.Similarly, RNA interference of PAK4 led to elevated expression of PTK6. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared to either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.

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“…In this section, the data were extracted by reading the full texts of the eight papers selected. [37][38][39][40][41][42][43][44] They investigated the impact and interaction of some different miRNAs on the expression of the MYC gene in PDAC. The extracted data were collected by two of the authors and were inserted into the extraction form.…”

Section: Data Extractionmentioning

confidence: 99%

<p>MicroRNAs Targeting MYC Expression: Trace of Hope for Pancreatic Cancer Therapy. A Systematic Review</p>

Shams¹,

Aghdaei²,

Behmanesh³

et al. 2020

CMAR

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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and a major health problem worldwide. There were no major advances in conventional treatments in inhibiting tumor progression and increasing patient survival time. In order to suppress mechanisms responsible for tumor cell development such as those with oncogenic roles, more advanced therapeutic strategies should be sought. One of the most important oncogenes of pancreatic cancer is the MYC gene. The overexpression of MYC can activate many tumorigenic processes such as cell proliferation and pancreatic cancer cell invasion. MiRNAs are important molecules that are confirmed by targeting mRNA transcripts to regulate the expression of the MYC gene. Therefore, restoring MYC-repressing miRNAs expression tends to be an effective method of treating MYC-driven cancers. Objective: The purpose of this study was to identify all validated microRNAs targeting C-MYC expression to inhibit PDAC progression by conducting a systematic review. Methods: In this systematic review study, the papers published between 2000 and 2020 in major online scientific databases including PubMed, Scopus, and Web of Science were screened, following inclusion and exclusion criteria. We extracted all the experimental studies that showed miRNAs could target the expression of the MYC gene in PDAC. Results: Eight papers were selected from a total of 89 papers. We found that six miRNAs (Let-7a, miR-145, miR-34a, miR-375, miR-494, and miR-148a) among the selected studies were validated for targeting MYC gene and three of them confirmed Let-7a as a direct MYC expression regulator in PC cells. Finally, we summarized the latest shreds of evidence of experimentally validated miRNAs targeting the MYC gene with respect to PDAC's therapeutic potential. Conclusion: Restoring the expression of MYC-repressing miRNAs tends to be an effective way to treat MYC-driven cancers such as PDAC. Several miRNAs have been proposed to target this oncogene via bioinformatics tools, but only a few have been experimentally validated for pancreatic cancer cells and models. Further studies should be conducted to find the interaction network of miRNA-MYC to develop more successful therapeutic strategies for PC, using the synergistic effects of these miRNAs.

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Exportin 1 (XPO1) inhibition leads to restoration of tumor suppressor miR-145 and consequent suppression of pancreatic cancer cell proliferation and migration

Cited by 45 publications

References 56 publications

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

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

Therapeutically actionable PAK4 is amplified, overexpressed and involved in bladder cancer progression

<p>MicroRNAs Targeting MYC Expression: Trace of Hope for Pancreatic Cancer Therapy. A Systematic Review</p>

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