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, 10 (21), 5212-5222
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AIB1 Predicts Tumor Response to Definitive Chemoradiotherapy and Prognosis in Cervical Squamous Cell Carcinoma

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AIB1 Predicts Tumor Response to Definitive Chemoradiotherapy and Prognosis in Cervical Squamous Cell Carcinoma

Zhenfeng Zhao et al. J Cancer.

Abstract

Amplified in breast cancer 1 (AIB1) gene, has been reported to be associated with biological malignancy in several cancers. However, the molecular status of the AIB1 gene in cervical cancer and the clinicopathological/prognostic significance of AIB1 expression in chemoradiotherapy (CRT) sensitivity have not been determined. In our present study, we found that the high expression of AIB1 was frequent detected in specimens of cervical cancer patients, and this was significantly correlated with CRT response (P = 0.014), clinical stage (P = 0.003), T status (P = 0.027), N status (P = 0.021), M status (P = 0.015) and progression-free survival (P < 0.001). Moreover, the clonogenic survival fraction and cell apoptosis experiments showed that knockdown of AIB1 substantially increased cervical cancer cells sensitivity to ionizing radiation (IR) or cisplatin/5-fluorouracil. Collectively, our results demonstrated that the high expression of AIB1 in cervical cancer cells contributes to the resistance to CRT, which provides the evidence that AIB1 may be a promising predictor of aggressive cervical cancer patients with poor response to CRT.

Keywords: AIB1; Cervical cancer; Linear-Quadratic Model; chemoradiotherapy; immunohistochemistry.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Expression of AIB1 in cervical cancer. A, The levels of AIB1 proteins in three cervical cancer cell lines and non-neoplastic cervical benign tissues examined by western blot. B, Normal cervical epithelial tissues (case 30) showed normal expression of AIB1 protein with a negative staining of AIB1 in the nuclei of all cervical epithelial cells (200×). C, Cervical squamous cell carcinoma (case 17) demonstrated normal expression of AIB1, in which all tumor cells showed negative staining of AIB1 (200×). D, Low expression of AIB1 was detected in cervical squamous cell carcinoma (case 34), in which less than 10% cancer cells showed low staining of AIB1 protein in the nuclei (200×). E, High expression of AIB1 was observed in cervical squamous cell carcinoma (case 21), in which 10~70% cancer cells demonstrated positive staining of AIB1 in the nuclei (200×). F, Another cervical squamous cell carcinoma (case 36) showed high expression of AIB1, in which more than 70% cancer cells showed high staining of AIB1 protein in the nuclei (200×).
Figure 2
Figure 2
Kaplan-Meier survival analysis of the AIB1 expression in total cohort and different subsets of cervical cancer patients. A, Total cohort (high expression =57cases, low expression=51 cases). B, M0 subset (high =38 cases, low = 43 cases). C, M1 subset (high =19 cases, low = 8 cases). D, N0 subset (high =32 cases, low = 39 cases). E, non-CR subset (high =39 cases, low = 23 cases). F, III+IV subset (high = 49 cases, low = 27 cases). The P value was calculated using a log-rank test.
Figure 3
Figure 3
Lentivirus-mediated AIB1 silencing enhances the chemosensitivities of cervical cancer cells. A-D, Dose-response curves of cisplatin or 5-Fu in SiHa and CaSki cells. AIB1-shRNA infected SiHa and CaSki cells showed more sensitive to cisplatin and 5-Fu than parental control cells. IC50 values are shown below. Data are Mean ± SD (n=3, P<0.05). E and F, After treated cells with cisplatin (IC30) or 5-Fu (IC30) for the 24 hours, the cleaved PARP and cleaved caspase-3 were detected in AIB1-shRNA and Luc-shRNA infected SiHa and CaSki cells by western blot.
Figure 4
Figure 4
AIB1 depletion increases the sensitivity of cervical cancer cells in response to ionizing radiation. A, Clonogenic survival of SiHa-shAIB1 and SiHa-shluc cells. Cells were exposed to increasing doses of radiation as indicated. After 12 days, colonies more than 50 cells were counted and survival curves were fitted according to the linear-quadratic mode. Results were obtained from three independent experiments. All results were from three independent experiments. B, After irradiated shAIB1-Siha and shluc-Siha cells with 3Gy or 0 Gy x-ray, the cleaved caspase-3 and cleaved PARP were detected by Western blot analysis. Experiments were performed three times and a representative result is shown. C, SiHa-shAIB1 and SiHa-shluc cells were initally treated with or without IR. 36 hours later, the proportion of apoptotic cells were determined by PI/Annexin V assay. Data described are the Means ± SD of triplicates (*P<0.05, Student's t-test).

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