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The Critical Role of Dysregulated RhoB Signaling Pathway in Radioresistance of Colorectal Cancer
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Xi An Jiao Tong Univ, Peoples R China.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Hebei Med Univ, Peoples R China.
Fourth Mil Med Univ, Peoples R China.
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2019 (English)In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 104, no 5, p. 1153-1164Article in journal (Refereed) Published
Abstract [en]

Purpose

To explore whether the Rho protein is involved in the radioresistance of colorectal cancer and investigate the underlying mechanisms.

Methods and Materials

Rho GTPase expression was measured after radiation treatment in colon cancer cells. RhoB knockout cell lines were established using the CRISPR/Cas9 system. In vitro assays and zebrafish embryos were used for analyzing radiosensitivity and invasive ability. Mass cytometry was used to detect RhoB downstream signaling factors. RhoB and Forkhead box M1 (FOXM1) expression were detected by immunohistochemistry in rectal cancer patients who participated in a radiation therapy trial.

Results

RhoB expression was related to radiation resistance. Complete depletion of the RhoB protein increased radiosensitivity and impaired radiation-enhanced metastatic potential in vitro and in zebrafish models. Probing signaling using mass cytometry–based single-cell analysis showed that the Akt phosphorylation level was inhibited by RhoB depletion after radiation. FOXM1 was downregulated in RhoB knockout cells, and the inhibition of FOXM1 led to lower survival rates and attenuated migration and invasion abilities of the cells after radiation. In the patients who underwent radiation therapy, RhoB overexpression was related to high FOXM1, late Tumor, Node, Metastasis stage, high distant recurrence, and poor survival independent of other clinical factors.

Conclusions

RhoB plays a critical role in radioresistance of colorectal cancer through Akt and FOXM1 pathways.

Place, publisher, year, edition, pages
Elsevier, 2019. Vol. 104, no 5, p. 1153-1164
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-159237DOI: 10.1016/j.ijrobp.2019.04.021ISI: 000475856100032PubMedID: 31039421Scopus ID: 2-s2.0-85068872792OAI: oai:DiVA.org:liu-159237DiVA, id: diva2:1341857
Note

Funding Agencies|Swedish Cancer Foundation; Swedish Research Council; Health Research Council in southeast Sweden; Oncology Clinics in Linkoping; National Natural Science Foundation of China [81872397]; State Key Laboratory Cancer Biology Open Foundation [CBSKL201730]; Xian Technology Foundation [201805094YX2SF28(6)]; International Science and Technology Cooperation Programme of China [2014DFA31150]; Medical Research Council [MR/N012097/1]; Cancer Research UK [C37/A12011, C37/A18784]; Breast Cancer Now [2012MayPR070, 2012NovPhD016]; Cancer Research UK Imperial Centre; Imperial Experimental Cancer Medicine Centre; National Institute for Health Research Imperial Biomedical Research Centre

Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-19Bibliographically approved

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Liu, NaCui, WeiyingqiGnosa, SebastianAli, ZaheerJensen, LasseJönsson, Jan-IngvarBlockhuys, StephaniePing, JieKopsida, MariaSun, Xiao-Feng
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Department of Clinical and Experimental MedicineFaculty of Medicine and Health SciencesDepartment of OncologyDivision of Cardiovascular MedicineDepartment of Clinical PharmacologyDivision of Hematopoiesis and Developmental BiologyDivision of Surgery, Orthopedics and Oncology
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