Correlation between mTOR Protein Expression and Cervical Cancer Risk: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 LIHui ¹ ,  WUSu-hui ² , YANZhong-hua ¹ , ZHOUBo-hui ² , SHIXiao-feng ² , ZHANGSu-yu ¹

1. Shanxi Medical University, Taiyuan 030001, China;
2. Department of Gynecology, Shanxi Academy of Medical Sciences, Shanxi Da Yi Hospital, Taiyuan 030032, China;

Corresponding?author：

WUSu-hui, Email: shwu1215@163.com

Keywords：

mTOR; Cervical cancer; Systematic review; Meta-analysis; Case-control study

DOI：

10.7507/1672-2531.20150153

Video：

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Objective To systematically review the correlation between mTOR protein expression and different clinical pathological features as well as the response to radiotherapy and chemotherapy of cervical cancer. Methods We electronically searched databases including The Cochrane Library (Issue 1, 2015), PubMed, EMbase, CNKI, CBM, VIP and WanFang Data from inception to April 2015 to collect case-control studies investigating the correlation between mTOR protein expression and different clinical pathological features as well as the response to radiotherapy and chemotherapy of cervical cancer. Two reviewers independently screened literature, extracted data and assessed the risk bias of the included studies. Then meta-analysis was performed using RevMan 5.2 software. Results A total of 8 case-control studies involving 591 patients were included. Among these cases, 365 cases were in the cervical cancer group, 135 cases were in the cervical intraepithelial neoplasia (CIN) group, and 91 cases were in the normal cervix tissue group. The results of meta-analysis showed that:(1) Compared with the normal cervix tissue group, mTOR protein was overexpressed in the cervical cancer group (OR=24.14, 95%CI 4.47 to 130.35, P=0.000 2) and the CIN group (OR=4.71, 95%CI 2.15 to 10.33, P=0.000 1); Compared with the CIN group, mTOR protein was overexpressed in the cervical cancer group (OR=5.12, 95%CI 2.96 to 8.86, P<0.000 01). (2) Compared with the non-lymphnode-metastasis group, mTOR protein was overexpressed in the lymph node metastasis group (OR=3.29, 95%CI 1.61 to 6.69, P=0.001); Compared with the FIGO I group, mTOR protein was overexpressed in the FIGO Ⅱ group (OR=3.00, 95%CI 1.49 to 6.04, P=0.002); Compared with the radiotherapy and chemotherapy responsive group, mTOR protein was overexpressed in the non-response group (OR=15.64, 95%CI 3.17 to 77.15, P=0.000 7). In addition, there was no significant difference between the medium/high differentiation group and low differentiation group (OR=1.70, 95%CI 0.75 to 3.81, P=0.20). Conclusion mTOR protein expression is associated with cervical cancer, and mTOR protein overexpression was associated with lymph node metastasis, higher FIGO and non-response to radiotherapy and chemotherapy. Due to the limited quantity and quality of the included studies, the above conclusion needs to be further verified by more high quality studies.

Citation： LIHui, WUSu-hui, YANZhong-hua, ZHOUBo-hui, SHIXiao-feng, ZHANGSu-yu. Correlation between mTOR Protein Expression and Cervical Cancer Risk: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2015, 15(8): 907-913. doi: 10.7507/1672-2531.20150153 Copy

1.	Arbyn M, Castellsague X, De Sanjose S, et al. Worldwide burden of cervical cancer in 2008. Ann Oncol, 2011, 22(12):2675-2686.
2.	Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin, 2014, 64(1):9-29.
3.	Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol, 2012, 62(3):147-172.
4.	Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer cell, 2007, 12(1):9-22.
5.	Ji J, Zheng PS. Activation of mTOR signaling pathway contributes to survival of cervical cancer cells. Gynecol Oncol, 2010, 117(1):103-108.
6.	Rashmi R, DeSelm C, Helms C, et al. AKT inhibitors promote cell death in cervical cancer through disruption of mTOR signaling and glucose uptake. PLoS One, 2014, 9(4):e92948.
7.	Kim MK, Kim TJ, Sung CO, et al. High expression of mTOR is associated with radiation resistance in cervical cancer. J Gynecol Oncol, 2010, 21(3):181-185.
8.	Gulhati P, Bowen KA, Liu J, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res, 2011, 71(9):3246-3256.
9.	Chen XG, Cheng HY, Pan TF, et al. mTOR regulate EMT through RhoA and Rac1 pathway in prostate cancer. Mol Carcinog, 2014, doi:10.1002/mc.22177.
10.	冀靜, 顧婷婷, 鄭鵬生. mTOR/P70S6K 信號通路在宮頸癌組織中的表達及其臨床意義. 西安交通大學學報:醫學版, 2010, 31(1):10-13.
11.	劉細友. mTOR 在宮頸癌中表達及其臨床意義的研究. 武漢:華中科技大學, 2008.
12.	盧丹, 錢靜, 孫飛, 等. PI3K, Akt, mTOR, p70S6K 基因在宮頸癌變過程中的表達及相關性研究. 中國現代醫學雜志, 2015, 25(2):46-51.
13.	潘啟紅. mTOR和M2-PK在宮頸鱗癌中的表達及相關性研究. 蚌埠:蚌埠醫學院, 2012.
14.	夏百榮, 孟凡玲, 盧北燕. mTOR, eIF4E, 4E-BP1在宮頸癌組織中的表達及臨床意義. 實用腫瘤學雜志, 2011, 25(4):301-305.
15.	Faried LS, Faried A, Kanuma T, et al. Predictive and prognostic role of activated mammalian target of rapamycin in cervical cancer treated with cisplatin-based neoadjuvant chemotherapy. Oncol Rep, 2006, 16(1):57-63.
16.	Kim MK, Kim TJ, Sung CO, et al. High expression of mTOR is associated with radiation resistance in cervical cancer. J Gynecol Oncol, 2010, 21(3):181-185.
17.	楊建萍, 李晟磊, 趙志華, 等. RNA干擾對宮頸癌Hela細胞中mTOR 4EBPl表達及細胞侵襲力的影響. 醫藥論壇雜志, 2013, 12:3.
18.	呂汕群, 姚婷婷, 黃諾潔, 等. mTOR和PTEN在宮頸鱗癌中的表達及意義. 中國醫藥指南, 2013, 11(18):1-3.
19.	Wells G, Shea B, ÓConnell D, et al. Newcastle-Ottawa Quality As-Sessment Scale-Case Control Studies. Available at:http://www.ohri.ca/programs/clinical-epidemiology/oxford-asp.
20.	Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J epidemiol, 2010, 25(9):603-605.
21.	Faried LS, Faried A, Kanuma T, et al. Expression of an activated mammalian target of rapamycin in adenocarcinoma of the cervix:A potential biomarker and molecular target therapy. Mol Carcinog, 2008, 47(6):446-457.
22.	國斌, 易斌, 魯開智. 哺乳動物雷帕霉素靶蛋白的研究進展. 醫學研究生學報, 2010, 23(8):876-879.
23.	Schulz R, Streller F, Scheel AH, et al. HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer. Cell death Dis, 2014, 5(1):e980.
24.	Andrikopoulou M, Salakos N, Deligeoroglou E, et al. The role of mTOR signaling pathway in premalignant and malignant cervical lesions. Eur J Gynaecol Oncol, 2014, 36(1):36-43.
25.	Hsieh AC, Liu Y, Edlind MP, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature, 2012, 485(7396):55-61.
26.	Zong H, Yin B, Zhou H, et al. Inhibition of mTOR pathway attenuates migration and invasion of gallbladder cancer via EMT inhibition. Mol Biol Rep, 2014, 41(7):4507-4512.
27.	Kwasnicki A, Jeevan D, Braun A, et al. Involvement of mTOR Signaling Pathways in Regulating Growth and Dissemination of Metastatic Brain Tumors via EMT. Anticancer Res, 2015, 35(2):689-696.
28.	Han B, Cui H, Kang L, et al. Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway. Tumor Biol, 2015:in press.
29.	Roy B, Pattanaik AK, Das J, et al. Role of PI3K/Akt/mTOR and MEK/ERK pathway in Concanavalin A induced autophagy in HeLa cells. Chem Biol Interact, 2014, 210:96-102.
30.	Molinolo AA, Marsh C, El Dinali M, et al. mTOR as a molecular target in HPV-associated oral and cervical squamous carcinomas. Clin Cancer Res, 2012, 18(9):2558-2568.

1. Arbyn M, Castellsague X, De Sanjose S, et al. Worldwide burden of cervical cancer in 2008. Ann Oncol, 2011, 22(12):2675-2686.
2. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin, 2014, 64(1):9-29.
3. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol, 2012, 62(3):147-172.
4. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer cell, 2007, 12(1):9-22.
5. Ji J, Zheng PS. Activation of mTOR signaling pathway contributes to survival of cervical cancer cells. Gynecol Oncol, 2010, 117(1):103-108.
6. Rashmi R, DeSelm C, Helms C, et al. AKT inhibitors promote cell death in cervical cancer through disruption of mTOR signaling and glucose uptake. PLoS One, 2014, 9(4):e92948.
7. Kim MK, Kim TJ, Sung CO, et al. High expression of mTOR is associated with radiation resistance in cervical cancer. J Gynecol Oncol, 2010, 21(3):181-185.
8. Gulhati P, Bowen KA, Liu J, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res, 2011, 71(9):3246-3256.
9. Chen XG, Cheng HY, Pan TF, et al. mTOR regulate EMT through RhoA and Rac1 pathway in prostate cancer. Mol Carcinog, 2014, doi:10.1002/mc.22177.
10. 冀靜, 顧婷婷, 鄭鵬生. mTOR/P70S6K 信號通路在宮頸癌組織中的表達及其臨床意義. 西安交通大學學報:醫學版, 2010, 31(1):10-13.
11. 劉細友. mTOR 在宮頸癌中表達及其臨床意義的研究. 武漢:華中科技大學, 2008.
12. 盧丹, 錢靜, 孫飛, 等. PI3K, Akt, mTOR, p70S6K 基因在宮頸癌變過程中的表達及相關性研究. 中國現代醫學雜志, 2015, 25(2):46-51.
13. 潘啟紅. mTOR和M2-PK在宮頸鱗癌中的表達及相關性研究. 蚌埠:蚌埠醫學院, 2012.
14. 夏百榮, 孟凡玲, 盧北燕. mTOR, eIF4E, 4E-BP1在宮頸癌組織中的表達及臨床意義. 實用腫瘤學雜志, 2011, 25(4):301-305.
15. Faried LS, Faried A, Kanuma T, et al. Predictive and prognostic role of activated mammalian target of rapamycin in cervical cancer treated with cisplatin-based neoadjuvant chemotherapy. Oncol Rep, 2006, 16(1):57-63.
16. Kim MK, Kim TJ, Sung CO, et al. High expression of mTOR is associated with radiation resistance in cervical cancer. J Gynecol Oncol, 2010, 21(3):181-185.
17. 楊建萍, 李晟磊, 趙志華, 等. RNA干擾對宮頸癌Hela細胞中mTOR 4EBPl表達及細胞侵襲力的影響. 醫藥論壇雜志, 2013, 12:3.
18. 呂汕群, 姚婷婷, 黃諾潔, 等. mTOR和PTEN在宮頸鱗癌中的表達及意義. 中國醫藥指南, 2013, 11(18):1-3.
19. Wells G, Shea B, ÓConnell D, et al. Newcastle-Ottawa Quality As-Sessment Scale-Case Control Studies. Available at:http://www.ohri.ca/programs/clinical-epidemiology/oxford-asp.
20. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J epidemiol, 2010, 25(9):603-605.
21. Faried LS, Faried A, Kanuma T, et al. Expression of an activated mammalian target of rapamycin in adenocarcinoma of the cervix:A potential biomarker and molecular target therapy. Mol Carcinog, 2008, 47(6):446-457.
22. 國斌, 易斌, 魯開智. 哺乳動物雷帕霉素靶蛋白的研究進展. 醫學研究生學報, 2010, 23(8):876-879.
23. Schulz R, Streller F, Scheel AH, et al. HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer. Cell death Dis, 2014, 5(1):e980.
24. Andrikopoulou M, Salakos N, Deligeoroglou E, et al. The role of mTOR signaling pathway in premalignant and malignant cervical lesions. Eur J Gynaecol Oncol, 2014, 36(1):36-43.
25. Hsieh AC, Liu Y, Edlind MP, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature, 2012, 485(7396):55-61.
26. Zong H, Yin B, Zhou H, et al. Inhibition of mTOR pathway attenuates migration and invasion of gallbladder cancer via EMT inhibition. Mol Biol Rep, 2014, 41(7):4507-4512.
27. Kwasnicki A, Jeevan D, Braun A, et al. Involvement of mTOR Signaling Pathways in Regulating Growth and Dissemination of Metastatic Brain Tumors via EMT. Anticancer Res, 2015, 35(2):689-696.
28. Han B, Cui H, Kang L, et al. Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway. Tumor Biol, 2015:in press.
29. Roy B, Pattanaik AK, Das J, et al. Role of PI3K/Akt/mTOR and MEK/ERK pathway in Concanavalin A induced autophagy in HeLa cells. Chem Biol Interact, 2014, 210:96-102.
30. Molinolo AA, Marsh C, El Dinali M, et al. mTOR as a molecular target in HPV-associated oral and cervical squamous carcinomas. Clin Cancer Res, 2012, 18(9):2558-2568.

Chinese Journal of Evidence-Based Medicine

Correlation between mTOR Protein Expression and Cervical Cancer Risk: A Meta-analysis

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