The Critical Role of Dysregulated RhoB Signaling Pathway in Radioresistance of Colorectal Cancer

Liu, Na; Cui, Weiyingqi; Jiang, Xia; Zhang, Zhiyong; Gnosa, Sebastian; Ali, Zaheer; Jensen, Lasse D.; Jönsson, Jan‐Ingvar; Blockhuys, Stéphanie; Lam, Eric W.‐F.; Zhao, Zhenze; Ping, Jie; Xie, Ning; Kopsida, Maria; Wang, Xin; Sun, Xiao‐Feng

doi:10.1016/j.ijrobp.2019.04.021

Cited by 21 publications

(18 citation statements)

References 31 publications

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“…Interestingly, the MEK inhibitor U0126 decreased FOXM1 protein levels in OVCA433, which is an ovarian cancer cell line with functional p53, but not in SKOV3, a p53-deleted ovarian cancer cell line; this suggests that functional p53 may be necessary for the MAPK/ERK pathway to regulate FOXM1 activity [ 206 ]. Studies in other cancers have suggested that the PI3K/AKT pathway, independent of the MAPK/ERK pathway, functions as a main activator of oncogenic FOXM1 activity [ 207 , 208 , 209 ].…”

Section: Foxm1 Is Overexpressed and Activated In Ovarian Cancermentioning

confidence: 99%

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

Liu

Barger

Karpf

2021

Cancers

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Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment.

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Section: Foxm1 Is Overexpressed and Activated In Ovarian Cancermentioning

confidence: 99%

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

Liu

Barger

Karpf

2021

Cancers

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“…As a well-known tumor suppressor, RhoB was reported to be relevant to cisplatin resistance [ 18 , 22 , 42 ]. Also, previous studies have reported that RhoB was targeted by miRNAs [ 20 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Hsa-miR-3178/RhoB/PI3K/Akt, a novel signaling pathway regulates ABC transporters to reverse gemcitabine resistance in pancreatic cancer

Huang

Wang

et al. 2022

Mol Cancer

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Background Although gemcitabine has been considered as the first-line drug for advanced pancreatic cancer (PC), development of resistance to gemcitabine severely limits the effectiveness of this chemotherapy, and the underlying mechanism of gemcitabine resistance remains unclear. Various factors, such as ATP binding cassette (ABC) transporters, microRNAs and their downstream signaling pathways are included in chemoresistance to gemcitabine. This study investigated the potential mechanisms of microRNAs and ABC transporters related signaling pathways for PC resistance to gemcitabine both in vivo and in vitro. Methods Immunohistochemistry and Western blotting were applied to detect the expression of ABC transporters. Molecular docking analysis was performed to explore whether gemcitabine interacted with ABC transporters. Gain-of-function and loss-of-function analyses were performed to investigate the functions of hsa-miR-3178 in vitro and in vivo. Bioinformatics analysis, Western blotting and dual-luciferase reporter assay were used to confirm the downstream regulatory mechanisms of hsa-miR-3178. Results We found that P-gp, BCRP and MRP1 were highly expressed in gemcitabine-resistant PC tissues and cells. Molecular docking analysis revealed that gemcitabine can bind to the ABC transporters. Hsa-miR-3178 was upregulated in gemcitabine resistance PANC-1 cells as compared to its parental PANC-1 cells. Moreover, we found that hsa-miR-3178 promoted gemcitabine resistance in PC cells. These results were also verified by animal experiments. RhoB was down-regulated in gemcitabine-resistant PC cells and it was a downstream target of hsa-miR-3178. Kaplan–Meier survival curve showed that lower RhoB expression was significantly associated with poor overall survival in PC patients. Rescue assays demonstrated that RhoB could reverse hsa-miR-3178-mediated gemcitabine resistance. Interestingly, hsa-miR-3178 promoted gemcitabine resistance in PC by activating the PI3K/Akt pathway-mediated upregulation of ABC transporters. Conclusions Our results indicate that hsa-miR-3178 promotes gemcitabine resistance via RhoB/PI3K/Akt signaling pathway-mediated upregulation of ABC transporters. These findings suggest that hsa-miR-3178 could be a novel therapeutic target for overcoming gemcitabine resistance in PC.

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“…Forkhead box M1 (FOXM1) is an oncogenic transcription factor that is always upregulated in various cancers including ccRCC [19,20]. Recently, FOXM1 has been reported to contribute to radioresistance in several carcinomas [21,22]. Meanwhile, it has also been demonstrated that FOXM1 was stabilized by CHEK2 and therefore enhanced the expression of FOXM1-targeted DNA repair genes [23].…”

Section: Linc01094 Increases Foxm1 Protein In Ccrcc By Acting As a Cementioning

confidence: 99%

LINC01094 triggers radio-resistance in clear cell renal cell carcinoma via miR-577/CHEK2/FOXM1 axis

Jiang

Yang

et al. 2020

Cancer Cell Int

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Background: Radioresistance is an obstacle to limit efficacy of radiotherapy. Meanwhile, long non-coding RNAs (lncRNAs) have been reported to affect radioresistance. Here, we aimed to investigate lncRNAs involving radioresistance development of clear cell renal cell carcinoma (ccRCC), the most frequent type of renal cell carcinoma (RCC). Methods: The mRNA and protein expressions of genes were measured via qRT-PCR and western blot. The relationships among genes were verified by RIP and luciferase reporter assay. The radioresistance of ccRCC cells was evaluated through clonogenic survival assay, MTT assay and TUNEL assay. Results: LINC01094 was over-expressed in ccRCC cell lines. LINC01094 expression was increased along with the radiation exposure time and the final stable level was 8 times of the initial level. Knockdown of LINC01094 resulted in enhanced radiosensitivity of ccRCC cells. Mechanically, LINC01094 was a ceRNA of CHEK2 by sponging miR-577. Also, the enhancement of LINC01094 on ccRCC radioresistance was mediated by CHEK2-stabilized FOXM1 protein. Conclusion: LINC01094 facilitates ccRCC radioresistance by targeting miR-577/CHEK2/FOXM1 axis, blazing a new trail for overcoming radioresistance in ccRCC.

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The Critical Role of Dysregulated RhoB Signaling Pathway in Radioresistance of Colorectal Cancer

Cited by 21 publications

References 31 publications

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

Hsa-miR-3178/RhoB/PI3K/Akt, a novel signaling pathway regulates ABC transporters to reverse gemcitabine resistance in pancreatic cancer

LINC01094 triggers radio-resistance in clear cell renal cell carcinoma via miR-577/CHEK2/FOXM1 axis

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