Gastrointestinal Cancer

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SU_5_2045 - FAK alleviates radiation-induced rectal injury through AKT Signaling Pathway

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

FAK alleviates radiation-induced rectal injury through AKT Signaling Pathway
W. Tu1, Y. Liu1, J. Ye2, J. Li1, Y. Ge1, Z. Le1, H. Ying1, S. Yao1, T. Chen1, and Q. Huang1; 1Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 2JiangSu Cancer Hospital, Nanjing, China

Purpose/Objective(s): Rectum is a dose-limiting organ in pelvic tumors radiotherapy. The assessing of radiosensitivity is good to improve individualized radiotherapy. Our previous study have showed increased FAK (focal adhesion kinase, PTK2) expression was related with radioresistance of intestinal epithelial cells. However, its molecular mechanism remains unclear. Here, we investigated the effect of FAK in radiation-induced rectal injury.

Materials/Methods: Peripheral blood samples of patients with colorectal cancer were collected prior to radiotherapy. Differentially expressed genes and copy number variations (CNV) were analyzed by microarray in blood samples. The CTCAE v3.0 toxicity grades was used assess the acute rectal injury. The intestinal epithelial cells is mostly the main targets for radiation damage. A normal human intestinal epithelial crypt cell line (HIEC) was used. The radiosensitivity of HIEC cells were detected by colony formation assay and flow cytometry. Further studies on AKT signaling- and apoptotic-related proteins were assessed by western blot. The inhibitors (VS-4718 and MK2206 2HCL) or siRNAs of FAK or AKT were used in the process of above detection. The rectum of C57BL/6N mices were X-irradiated locally with a single dose of 25Gy, and following experiments including hematoxylin-eosin (HE) staining, real-time PCR and immunohistochemistry (IHC). In addition, the effect of FAK-AKT on radiation-induced injury were investigated by the administration of AKT inhibitor after irradiation.

Results: FAK mRNA was highly expressed in the mild rectal injury patients samples compared with the severe injury patients samples. In addition, the CNV amplification was located on chromosome 8p24.3, which was related closely with FAK. Further study demonstrated FAK-silenced HIEC cells were more radiosensitive by colony survival and apoptosis assay. The expression of γH2AX involved in DNA damage and repair increased either at 6 h or at 24 h after irradiation treatment. Further functional assays revealed that depressed AKT, increased cytochrome C and cleaved caspase-3 in FAK-silenced HIEC cells. In vivo, radiation-induced apoptosis of crypt cells are under analysed with or without AKT inhibition.

Conclusion: The effect of FAK was known in cancer cells. In current study, our data showed that FAK expression was consistent mild radiation-induced rectal injury. These findings demonstrated that FAK reduced the radiosensitivity of intestinal epithelial cells, which may be related with AKT signaling pathway and apoptotic-related proteins. In summary, further studies based on better understanding of FAK may be benefit to predict and prevent radiation-induced normal tissue injury.

Author Disclosure: W. Tu: None. Y. Liu: None. H. Ying: None. Q. Huang: None.

Wenzhi Tu, PhD

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