Abstract
Laryngeal squamous cell carcinoma (LSCC) is the second most common malignancy of the head and neck region in the USA with a declining 5-year survival rate. Paclitaxel resistance of tumors including LSCC still stands as a vital cause for poor clinical outcome in patients. In the current study, our aim was to explore the expressions of ATP-binding cassette transporters and stemness associated genes in human epithelial type 2 (Hep-2) cells with paclitaxel resistance. Resistant cells were developed via treatment with increasing doses of paclitaxel to acquire four sub-lines resistant to one-, two-, four-, and eightfold concentrations of paclitaxel (1×, 2×, 4×, 8×). Then, we profiled the expressions of ten selected ABC transporters (ABCA5, ABCB1, ABCB6, ABCC1, ABCC2, ABCC3, ABCC5, ABCC10, ABCF2, and ABCG2) and four stem cell markers (SOX2, OCT4, KLF, and CXCR4) using quantitative real time polymerase chain reaction in paclitaxel resistant cells to look for a link between these markers and chemoresistance. We demonstrated that ABCB1 and ABCG2 expressions gradually elevated and reached a maximum level in Taxol 8× cells. Considering stem cell markers, KLF4 expression elevated significantly, as soon as parental cells acquired resistance to the lowest dose of paclitaxel and its expression elevated stepwise. Expression levels of other tested ATP-binding cassette transporters and stem cell markers also elevated, although at different steps of paclitaxel resistance acquisition. Our findings suggest that higher expressions of ABCB1, ABCG2, and KLF4 might be considered as putative indicators for paclitaxel resistance in LSCC patients.
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References
American Cancer Society. Cancer facts & figures 2020. American Cancer Society. https://www.cancer.org
American Cancer Society. Laryngeal and hypopharyngeal cancer 2020. http://www.cancer.org
Yilmaz SS, Guzel E, Karatas OF, Yilmaz M, Creighton CJ, Ozen M (2015) MiR-221 as a pre- and postoperative plasma biomarker for larynx cancer patients. Laryngoscope 125(12):E377–EE81
American Cancer Society. Laryngeal and hypopharyngeal cancer 2018. http://www.cancer.org
Karatas OF, Yuceturk B, Suer I, Yilmaz M, Cansiz H, Ittmann M et al (2016) The role of miR-145 in human laryngeal squamous cell carcinoma. Head Neck 38(2):260–266
Sharom FJ (2008) ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics 9(1):105–127
Karatas OF, Guzel E, Duz MB, Ittmann M, Ozen M (2016) The role of ATP-binding cassette transporter genes in the progression of prostate cancer. Prostate 76(5):434–444
Fletcher JI, Haber M, Henderson MJ, Norris MD (2010) ABC transporters in cancer: more than just drug efflux pumps. Nat Rev Cancer 10(2):147–156
Guzel E, Karatas OF, Duz MB, Solak M, Ittmann M, Ozen M (2014) Differential expression of stem cell markers and ABCG2 in recurrent prostate cancer. Prostate 74(15):1498–1505
Saini V, Hose CD, Monks A, Nagashima K, Han B, Newton DL et al (2012) Identification of CBX3 and ABCA5 as putative biomarkers for tumor stem cells in osteosarcoma. PLoS One 7(8):e41401
Barbet R, Peiffer I, Hutchins JR, Hatzfeld A, Garrido E, Hatzfeld JA (2012) Expression of the 49 human ATP binding cassette (ABC) genes in pluripotent embryonic stem cells and in early- and late-stage multipotent mesenchymal stem cells: possible role of ABC plasma membrane transporters in maintaining human stem cell pluripotency. Cell Cycle 11(8):1611–1620
Thomas ML, Coyle KM, Sultan M, Vaghar-Kashani A, Marcato P (2014) Chemoresistance in cancer stem cells and strategies to overcome resistance. Chemotherapy 3(1):125
Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB (2003) Mechanisms of Taxol resistance related to microtubules. Oncogene 22(47):7280–7295
Xu CZ, Xie J, Jin B, Chen XW, Sun ZF, Wang BX et al (2013) Gene and microRNA expression reveals sensitivity to paclitaxel in laryngeal cancer cell line. Int J Clin Exp Pathol 6(7):1351–1361
Xu CZ, Shi RJ, Chen D, Sun YY, Wu QW, Wang T et al (2013) Potential biomarkers for paclitaxel sensitivity in hypopharynx cancer cell. Int J Clin Exp Pathol 6(12):2745–2756
Dong JR, Guo N, Zhao JP, Liu PD, Feng HH, Li Y (2013) Inhibition of nemo-like kinase increases taxol sensitivity in laryngeal cancer. Asian Pac J Cancer Prev 14(12):7137–7141
Duz MB, Karatas OF (2020) Expression profile of stem cell markers and ABC transporters in 5-fluorouracil resistant Hep-2 cells. Mol Biol Rep 47(7):5431–5438
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408
Bradford CR, Ferlito A, Devaney KO, Mäkitie AA, Rinaldo A (2020) Prognostic factors in laryngeal squamous cell carcinoma. Laryngoscope Investig Otolaryngol 5(1):74–81
National Cancer Institute. A snapshot of head and neck cancer incidence and mortality 2015. http://www.cancer.gov/research/progress/snapshots/headandneck
Gornstein E, Schwarz TL (2014) The paradox of paclitaxel neurotoxicity: mechanisms and unanswered questions. Neuropharmacology 76(Pt A):175–183
Suer I, Karatas OF, Yuceturk B, Yilmaz M, Guven G, Oz B et al (2014) Characterization of stem-like cells directly isolated from freshly resected laryngeal squamous cell carcinoma specimens. Curr Stem Cell Res Ther 9(4):347–353
Wang B, Li S, Meng X, Shang H, Guan Y (2015) Inhibition of mdr1 by G-quadruplex oligonucleotides and reversal of paclitaxel resistance in human ovarian cancer cells. Tumour Biol 36(8):6433–6443
Xu F, Wang F, Yang T, Sheng Y, Zhong T, Chen Y (2014) Differential drug resistance acquisition to doxorubicin and paclitaxel in breast cancer cells. Cancer Cell Int 14(1):538
Li L, Jiang AC, Dong P, Wan Y, Yu ZW (2007) The characteristics of Hep-2 cell with multiple drug resistance induced by Taxol. Otolaryngol Head Neck Surg 137(4):659–664
Allen JD, Brinkhuis RF, van Deemter L, Wijnholds J, Schinkel AH (2000) Extensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance. Cancer Res 60(20):5761–5766
Hembruff SL, Laberge ML, Villeneuve DJ, Guo B, Veitch Z, Cecchetto M et al (2008) Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance. BMC Cancer 8:318
Abdullah LN, Chow EK (2013) Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2(1):3
Setia N, Abbas O, Sousa Y, Garb JL, Mahalingam M (2012) Profiling of ABC transporters ABCB5, ABCF2 and nestin-positive stem cells in nevi, in situ and invasive melanoma. Mod Pathol 25(8):1169–1175
Lim YC, Oh SY, Cha YY, Kim SH, Jin X, Kim H (2011) Cancer stem cell traits in squamospheres derived from primary head and neck squamous cell carcinomas. Oral Oncol 47(2):83–91
Yi XJ, Zhao YH, Qiao LX, Jin CL, Tian J, Li QS (2015) Aberrant Wnt/β-catenin signaling and elevated expression of stem cell proteins are associated with osteosarcoma side population cells of high tumorigenicity. Mol Med Rep 12(4):5042–5048
Fujita T, Chiwaki F, Takahashi RU, Aoyagi K, Yanagihara K, Nishimura T et al (2015) Identification and characterization of CXCR4-positive gastric cancer stem cells. PLoS One 10(6):e0130808
Zhang W, Wang X, Yue K, Liu S, Liu X (2015) Construction of a CXCL12-KDEL fusion gene to inhibit head and neck squamous cell carcinoma metastasis by intracellular sequestration of CXCR4. Biomed Res Int 2015:195828
Craveiro V, Yang-Hartwich Y, Holmberg JC, Sumi NJ, Pizzonia J, Griffin B et al (2013) Phenotypic modifications in ovarian cancer stem cells following Paclitaxel treatment. Cancer Med 2(6):751–762
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Duz, M.B., Karatas, O.F. Differential expression of ABCB1, ABCG2, and KLF4 as putative indicators for paclitaxel resistance in human epithelial type 2 cells. Mol Biol Rep 48, 1393–1400 (2021). https://doi.org/10.1007/s11033-021-06167-6
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DOI: https://doi.org/10.1007/s11033-021-06167-6