Activation of the LKB1‑SIK1 signaling pathway inhibits the TGF‑β‑mediated epithelial‑mesenchymal transition and apoptosis resistance of ovarian carcinoma cells Retraction in /10.3892/mmr.2024.13180

Hong,Bo; Zhang,Jianmei; Yang,Wenlan

doi:10.3892/mmr.2017.8229

Activation of the LKB1‑SIK1 signaling pathway inhibits the TGF‑β‑mediated epithelial‑mesenchymal transition and apoptosis resistance of ovarian carcinoma cells

Retraction in: /10.3892/mmr.2024.13180

Authors:
- Bo Hong
- Jianmei Zhang
- Wenlan Yang
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Affiliations: Department of Gynecology, Haidian Maternal and Child Healthcare Center, Beijing 320010, P.R. China
Published online on: December 8, 2017 https://doi.org/10.3892/mmr.2017.8229
Pages: 2837-2844
Copyright: © Hong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ovarian cancer is the most common and lethal type of gynecological malignancy, due to its invasiveness. The present study aimed to analyze the molecular mechanism underlying chemoresistance in ovarian carcinoma cells, which may lead to local migration toward adjacent tissues and long‑distance metastasis to other organs. A total of 12 patients with ovarian fibroma were used to evaluate chemoresistance and chemosensitivity. The sensitivity and resistance of ovarian carcinoma cells was measured using apoptosis analysis, morphological observation, survival rate analysis, immunohistochemistry and immunostaining. The mechanism underlying the interaction between the epithelial‑mesenchymal transition (EMT) and liver kinase B1 (LKB1)‑salt‑inducible kinase 1 (SIK1) signaling pathways was additionally investigated in ovarian carcinoma. The results of the present study demonstrated that ovarian carcinoma cells isolated from patients exhibited apoptosis resistance. Inhibition of TGF‑β expression led to an inhibition of growth, migration and invasion, in addition to a promotion of apoptosis, in ovarian carcinoma cells treated with paclitaxel. Studies have indicated that the LKB1‑SIK1 signaling pathway may be suppressed in ovarian carcinoma cells compared with normal ovarian cells, leading to activation of the EMT signaling pathway. The results of the present study demonstrated that upregulation of LKB1 promoted SIK1 expression and markedly suppressed the growth and aggressiveness of ovarian cancer cells. Upregulation of LKB1 additionally promoted apoptosis in ovarian carcinoma cells. In addition, the results of the present study demonstrated that the knockdown of LKB1 further promoted the expression of transforming growth factor‑β and EMT, which downregulated the chemosensitivity of ovarian carcinoma cells. Additionally, overexpression of LKB1 in ovarian carcinoma cells increased chemosensitivity, resulting in a significant inhibition of migration and invasion. The present findings indicated that the enhancement of LKB1‑SIK1 suppressed the growth and aggressiveness of ovarian carcinoma cells isolated from clinical patients, which subsequently contributed to an inhibition of metastatic potential. In conclusion, targeting the LKB1‑SIK1 signaling pathway to inhibit EMT may provide potential therapeutic benefits in ovarian carcinoma.

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1	Heidemann LN, Hartwell D, Heidemann CH and Jochumsen KM: The relation between endometriosis and ovarian cancer - a review. Acta Obstet Gynecol Scand. 93:20–31. 2014. View Article : Google Scholar : PubMed/NCBI
2	Petrillo M, Legge F, Ferrandina G, Monterisi A, Pedone Anchora L and Scambia G: Fertility-sparing surgery in ovarian cancer extended beyond the ovaries: A case report and review of the literature. Gynecol Obstet Invest. 77:1–5. 2014. View Article : Google Scholar : PubMed/NCBI
3	Kobayashi O, Sugiyama Y, Cho H, Tsuburaya A, Sairenji M, Motohashi H and Yoshikawa T: Clinical and pathological study of gastric cancer with ovarian metastasis. Int J Clin Oncol. 8:67–71. 2003. View Article : Google Scholar : PubMed/NCBI
4	Raavé R, de Vries RB, Massuger LF, van Kuppevelt TH and Daamen WF: Drug delivery systems for ovarian cancer treatment: A systematic review and meta-analysis of animal studies. PeerJ. 3:e14892015. View Article : Google Scholar : PubMed/NCBI
5	Gallardo-Rincón D, Espinosa-Romero R, Muñoz WR, Mendoza-Martínez R, Villar-Álvarez SD, Oñate-Ocaña L, Isla-Ortiz D, Márquez-Manríquez JP, Apodaca-Cruz Á and Meneses-García A: Epidemiological overview, advances in diagnosis, prevention, treatment and management of epithelial ovarian cancer in Mexico. Salud Publica Mex. 58:302–308. 2016. View Article : Google Scholar : PubMed/NCBI
6	Ganesan P, Kumar L, Hariprasad R, Gupta A, Dawar R and Vijayaraghavan M: Improving care in ovarian cancer: The role of a clinico-pathological meeting. Natl Med J India. 21:225–227. 2008.PubMed/NCBI
7	Jin F, Li HS, Zhao L, Wei YJ, Zhang H, Guo YJ, Pang R, Jiang XB and Zhao HY: Expression of anti-apoptotic and multi-drug resistance-associated protein genes in cancer stem cell isolated from TJ905 glioblastoma multiforme cell line. Zhonghua Yi Xue Za Zhi. 88:2312–2316. 2008.(In Chinese). PubMed/NCBI
8	Hamada S, Masamune A, Miura S, Satoh K and Shimosegawa T: miR-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and pro-apoptotic regulator BAX. Cell Signal. 26:179–185. 2014. View Article : Google Scholar : PubMed/NCBI
9	Shiota M, Yokomizo A and Naito S: Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer. Endocr Relat Cancer. 19:R243–R253. 2012. View Article : Google Scholar : PubMed/NCBI
10	Yang TM, Barbone D, Fennell DA and Broaddus VC: Bcl-2 family proteins contribute to apoptotic resistance in lung cancer multicellular spheroids. Am J Respir Cell Mol Biol. 41:14–23. 2009. View Article : Google Scholar : PubMed/NCBI
11	Zaffaroni N, Pennati M, Colella G, Perego P, Supino R, Gatti L, Pilotti S, Zunino F and Daidone MG: Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer. Cell Mol Life Sci. 59:1406–1412. 2002. View Article : Google Scholar : PubMed/NCBI
12	Xing H, Weng D, Chen G, Tao W, Zhu T, Yang X, Meng L, Wang S, Lu Y and Ma D: Activation of fibronectin/PI-3K/Akt2 leads to chemoresistance to docetaxel by regulating survivin protein expression in ovarian and breast cancer cells. Cancer Lett. 261:108–119. 2008. View Article : Google Scholar : PubMed/NCBI
13	Liguang Z, Peishu L, Hongluan M, Hong J, Rong W, Wachtel MS and Frezza EE: Survivin expression in ovarian cancer. Exp Oncol. 29:121–125. 2007.PubMed/NCBI
14	Cheng JC, Auersperg N and Leung PC: TGF-beta induces serous borderline ovarian tumor cell invasion by activating EMT but triggers apoptosis in low-grade serous ovarian carcinoma cells. PLoS One. 7:e424362012. View Article : Google Scholar : PubMed/NCBI
15	Song J: EMT or apoptosis: A decision for TGF-beta. Cell Res. 17:289–290. 2007. View Article : Google Scholar : PubMed/NCBI
16	Gal A, Sjöblom T, Fedorova L, Imreh S, Beug H and Moustakas A: Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis. Oncogene. 27:1218–1230. 2008. View Article : Google Scholar : PubMed/NCBI
17	Chorna I, Bilyy R, Datsyuk L and Stoika R: Comparative study of human breast carcinoma MCF-7 cells differing in their resistance to doxorubicin: effect of ionizing radiation on apoptosis and TGF-beta production. Exp Oncol. 26:111–117. 2004.PubMed/NCBI
18	Yao YH, Cui Y, Qiu XN, Zhang LZ, Zhang W, Li H and Yu JM: Attenuated LKB1-SIK1 signaling promotes epithelial-mesenchymal transition and radioresistance of non-small cell lung cancer cells. Chin J Cancer. 35:502016. View Article : Google Scholar : PubMed/NCBI
19	Kruger W, Jung R, Kröger N, Gutensohn K, Fiedler W, Neumaier M, Jänicke F, Wagener C and Zander AR: Sensitivity of assays designed for the detection of disseminated epithelial tumor cells is influenced by cell separation methods. Clin Chem. 46:435–436. 2000.PubMed/NCBI
20	Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, Yan PS, Huang TH and Nephew KP: Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 68:4311–4320. 2008. View Article : Google Scholar : PubMed/NCBI
21	Wai-Hoe L, Wing-Seng L, Ismail Z and Lay-Harn G: SDS-PAGE-based quantitative assay for screening of kidney stone disease. Biol Proced Online. 11:145–160. 2009. View Article : Google Scholar : PubMed/NCBI
22	Scherer O, Maeß MB, Lindner S, Garscha U, Weinigel C, Rummler S, Werz O and Lorkowski S: A procedure for efficient non-viral siRNA transfection of primary human monocytes using nucleofection. J Immunol Methods. 422:118–124. 2015. View Article : Google Scholar : PubMed/NCBI
23	Renshaw A and Elsheikh TM: A validation study of the Focalpoint GS imaging system for gynecologic cytology screening. Cancer Cytopathol. 121:737–738. 2013. View Article : Google Scholar : PubMed/NCBI
24	Kobayashi M, Chiba A, Izawa H, Yanagida E, Okamoto M, Shimodaira S, Yonemitsu Y, Shibamoto Y, Suzuki N and Nagaya M: DC-vaccine study group at the Japan Society of Innovative Cell Ther: The feasibility and clinical effects of dendritic cell-based immunotherapy targeting synthesized peptides for recurrent ovarian cancer. J Ovarian Res. 7:482014. View Article : Google Scholar : PubMed/NCBI
25	Ebell MH, Culp MB and Radke TJ: A systematic review of symptoms for the diagnosis of ovarian cancer. Am J Prev Med. 50:384–394. 2016. View Article : Google Scholar : PubMed/NCBI
26	Barrett CL, DeBoever C, Jepsen K, Saenz CC, Carson DA and Frazer KA: Systematic transcriptome analysis reveals tumor-specific isoforms for ovarian cancer diagnosis and therapy. Proc Natl Acad Sci USA. 112:pp. E3050–E3057. 2015; View Article : Google Scholar : PubMed/NCBI
27	Duda K, Cholewa H, Łabuzek K, Boratyn-Nowicka A and Okopień B: Novel strategies of ovarian cancer treatment. Pol Merkur Lekarski. 39:337–342. 2015.(In Polish). PubMed/NCBI
28	Monteith GR: Prostate cancer cells alter the nature of their calcium influx to promote growth and acquire apoptotic resistance. Cancer Cell. 26:1–2. 2014. View Article : Google Scholar : PubMed/NCBI
29	Moody SE, Schinzel AC, Singh S, Izzo F, Strickland MR, Luo L, Thomas SR, Boehm JS, Kim SY, Wang ZC and Hahn WC: PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling. Oncogene. 34:2061–2071. 2015. View Article : Google Scholar : PubMed/NCBI
30	Haslehurst AM, Koti M, Dharsee M, Nuin P, Evans K, Geraci J, Childs T, Chen J, Li J, Weberpals J, et al: EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer. 12:912012. View Article : Google Scholar : PubMed/NCBI
31	Thériault BL, Shepherd TG, Mujoomdar ML and Nachtigal MW: BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells. Carcinogenesis. 28:1153–1162. 2007. View Article : Google Scholar : PubMed/NCBI
32	Takai M, Terai Y, Kawaguchi H, Ashihara K, Fujiwara S, Tanaka T, Tsunetoh S, Tanaka Y, Sasaki H, Kanemura M, et al: The EMT (epithelial-mesenchymal-transition)-related protein expression indicates the metastatic status and prognosis in patients with ovarian cancer. J Ovarian Res. 7:762014. View Article : Google Scholar : PubMed/NCBI
33	Lili LN, Matyunina LV, Walker LD, Wells SL, Benigno BB and McDonald JF: Molecular profiling supports the role of epithelial-to-mesenchymal transition (EMT) in ovarian cancer metastasis. J Ovarian Res. 6:492013. View Article : Google Scholar : PubMed/NCBI
34	Ford CE, Jary E, Ma SS, Nixdorf S, Heinzelmann-Schwarz VA and Ward RL: The Wnt gatekeeper SFRP4 modulates EMT, cell migration and downstream Wnt signalling in serous ovarian cancer cells. PLoS One. 8:e543622013. View Article : Google Scholar : PubMed/NCBI
35	Huang RY, Chung VY and Thiery JP: Targeting pathways contributing to epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer. Curr Drug Targets. 13:1649–1653. 2012. View Article : Google Scholar : PubMed/NCBI
36	Mao Y, Xu J, Li Z, Zhang N, Yin H and Liu Z: The role of nuclear β-catenin accumulation in the Twist2-induced ovarian cancer EMT. PLoS One. 8:e782002013. View Article : Google Scholar : PubMed/NCBI
37	Jiang H, Lin X, Liu Y, Gong W, Ma X, Yu Y, Xie Y, Sun X, Feng Y, Janzen V and Chen T: Transformation of epithelial ovarian cancer stemlike cells into mesenchymal lineage via EMT results in cellular heterogeneity and supports tumor engraftment. Mol Med. 18:1197–1208. 2012. View Article : Google Scholar : PubMed/NCBI
38	Tang J, Wang J, Fan L, Li X, Liu N, Luo W, Wang J and Wang Y and Wang Y: cRGD inhibits vasculogenic mimicry formation by down-regulating uPA expression and reducing EMT in ovarian cancer. Oncotarget. 7:24050–24062. 2016. View Article : Google Scholar : PubMed/NCBI
39	Cha Y, Kim DK, Hyun J, Kim SJ and Park KS: TCEA3 binds to TGF-beta receptor I and induces Smad-independent, JNK-dependent apoptosis in ovarian cancer cells. Cell Signal. 25:1245–1251. 2013. View Article : Google Scholar : PubMed/NCBI
40	Tanwar PS, Mohapatra G, Chiang S, Engler DA, Zhang L, Kaneko-Tarui T, Ohguchi Y, Birrer MJ and Teixeira JM: Loss of LKB1 and PTEN tumor suppressor genes in the ovarian surface epithelium induces papillary serous ovarian cancer. Carcinogenesis. 35:546–553. 2014. View Article : Google Scholar : PubMed/NCBI
41	Liu T, Qin W, Hou L and Huang Y: MicroRNA-17 promotes normal ovarian cancer cells to cancer stem cells development via suppression of the LKB1-p53-p21/WAF1 pathway. Tumour Biol. 36:1881–1893. 2015. View Article : Google Scholar : PubMed/NCBI
42	Chen JL, Chen F, Zhang TT and Liu NF: Suppression of SIK1 by miR-141 in human ovarian cancer cell lines and tissues. Int J Mol Med. 37:1601–1610. 2016. View Article : Google Scholar : PubMed/NCBI