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Published in: Cancer Cell International 1/2018

Open Access 01-12-2018 | Primary research

Overexpression of LASS2 inhibits proliferation and causes G0/G1 cell cycle arrest in papillary thyroid cancer

Authors: Feng Zeng, Liangliang Huang, Xiaoming Cheng, Xiaoli Yang, Taolang Li, Guoli Feng, Yingqi Tang, Yan Yang

Published in: Cancer Cell International | Issue 1/2018

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Abstract

Background

The aim of this study was to investigate the role of LAG1 longevity-assurance homologue 2 (LASS2) in papillary thyroid cancer (PTC).

Methods

Immunohistochemistry staining was conducted to explore the expression levels of LASS2 in PTC tissues and adjacent normal thyroid tissues and nodular goiter tissues. Western blotting and RT-qPCR were performed to explore the expression levels of LASS2 in three PTC cell lines (TPC-1, K1, BCPAP). An Adv-LASS2-GFP recombinant adenovirus vector was constructed and transduced into BCPAP cells. Then CCK-8 assay, colony formation assay, cell cycle distribution, and apoptosis were performed. Western blotting was used to examine the expression of p21, cyclin D1, cyclin-dependent kinase 4, p53 and p-p53.

Results

LASS2 was downregulated in PTC tissues compared with adjacent thyroid tissues or nodular goiter tissues. In addition, the expression of LASS2 was found to be associated with TNM stage and lymph node metastasis. BCPAP cells expressed the lowest LASS2 compared to TPC-1 cells or K1 cells. Overexpression of LASS2 significantly inhibited proliferation, promoted apoptosis and caused G0/G1 cell cycle arrest in BCPAP cells. Furthermore, overexpression of LASS2 significantly increased the expression of p21, inhibited the expression of cyclin D1 and cyclin-dependent kinase 4, and increased the expression of p-p53, but did not effect the expression of p53 in BCPAP cells.

Conclusion

Our findings indicate that overexpression of LASS2 inhibits PTC cell proliferation, promotes apoptosis and causes G0/G1 cell cycle arrest via a p53-dependent pathway. Thus, LASS2 may serve as a novel biomarker in PTC.
Literature
1.
2.
go back to reference Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.CrossRef Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.CrossRef
3.
go back to reference Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA. 2006;295(18):2164–7.CrossRef Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA. 2006;295(18):2164–7.CrossRef
4.
go back to reference Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13(3):184–99.CrossRef Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13(3):184–99.CrossRef
6.
go back to reference Celestino R, Nome T, Pestana A, Hoff AM, Gonçalves AP, Pereira L, Cavadas B, Eloy C, Bjøro T, Sobrinho-Simões M, Skotheim RI, Soares P. CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension. BMC Cancer. 2018;18(1):68.CrossRef Celestino R, Nome T, Pestana A, Hoff AM, Gonçalves AP, Pereira L, Cavadas B, Eloy C, Bjøro T, Sobrinho-Simões M, Skotheim RI, Soares P. CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension. BMC Cancer. 2018;18(1):68.CrossRef
7.
go back to reference Razavi SA, Modarressi MH, Yaghmaei P, Tavangar SM, Hedayati M. Circulating levels of PTEN and KLLN in papillary thyroid carcinoma: can they be considered as novel diagnostic biomarkers. Endocrine. 2017;57(3):428–35.CrossRef Razavi SA, Modarressi MH, Yaghmaei P, Tavangar SM, Hedayati M. Circulating levels of PTEN and KLLN in papillary thyroid carcinoma: can they be considered as novel diagnostic biomarkers. Endocrine. 2017;57(3):428–35.CrossRef
8.
go back to reference Krishnamurthy A, Ramshankar V, Murherkar K, Vidyarani S, Raghunandhan GC, Das A, Desai PB, Albert K. Role and relevance of BRAF mutations in risk stratifying patients of papillary thyroid cancers along with a review of literature. Indian J Cancer. 2017;54(1):372–8.CrossRef Krishnamurthy A, Ramshankar V, Murherkar K, Vidyarani S, Raghunandhan GC, Das A, Desai PB, Albert K. Role and relevance of BRAF mutations in risk stratifying patients of papillary thyroid cancers along with a review of literature. Indian J Cancer. 2017;54(1):372–8.CrossRef
9.
go back to reference Pan H, Qin WX, Huo KK, Wan DF, Yu Y, Xu ZG, Hu QD, Gu KT, Zhou XM, Jiang HQ, Zhang PP, Huang Y, Li YY, Gu JR. Cloning, mapping, and characterization of a human homologue of the yeast longevity assurance gene LAG1. Genomics. 2001;77(1–2):58–64.CrossRef Pan H, Qin WX, Huo KK, Wan DF, Yu Y, Xu ZG, Hu QD, Gu KT, Zhou XM, Jiang HQ, Zhang PP, Huang Y, Li YY, Gu JR. Cloning, mapping, and characterization of a human homologue of the yeast longevity assurance gene LAG1. Genomics. 2001;77(1–2):58–64.CrossRef
10.
go back to reference Seitz AP, Grassmé H, Edwards MJ, Pewzner-Jung Y, Gulbins E. Ceramide and sphingosine in pulmonary infections. Biol Chem. 2015;396(6–7):611–20.PubMed Seitz AP, Grassmé H, Edwards MJ, Pewzner-Jung Y, Gulbins E. Ceramide and sphingosine in pulmonary infections. Biol Chem. 2015;396(6–7):611–20.PubMed
11.
go back to reference Ma C, Liu Y, Zheng J, Fang W, You J, Wang J, Cui X, Wu B. Identification of tumor metastasis related gene TMSG-1 by mRNA differential display. Sci China C Life Sci. 2002;45(5):553–60.CrossRef Ma C, Liu Y, Zheng J, Fang W, You J, Wang J, Cui X, Wu B. Identification of tumor metastasis related gene TMSG-1 by mRNA differential display. Sci China C Life Sci. 2002;45(5):553–60.CrossRef
12.
go back to reference Wang H, Zuo Y, Ding M, Ke C, Yan R, Zhan H, Liu J, Wang W, Li N, Wang J. LASS2 inhibits growth and invasion of bladder cancer by regulating ATPase activity. Oncol Lett. 2017;13(2):661–8.CrossRef Wang H, Zuo Y, Ding M, Ke C, Yan R, Zhan H, Liu J, Wang W, Li N, Wang J. LASS2 inhibits growth and invasion of bladder cancer by regulating ATPase activity. Oncol Lett. 2017;13(2):661–8.CrossRef
13.
go back to reference Xu X, Liu B, Zou P, Zhang Y, You J, Pei F. Silencing of LASS2/TMSG1 enhances invasion and metastasis capacity of prostate cancer cell. J Cell Biochem. 2014;115(4):731–43.CrossRef Xu X, Liu B, Zou P, Zhang Y, You J, Pei F. Silencing of LASS2/TMSG1 enhances invasion and metastasis capacity of prostate cancer cell. J Cell Biochem. 2014;115(4):731–43.CrossRef
14.
go back to reference Mei F, You J, Liu B, Zhang M, Liu J, Zhang B, Pei F. LASS2/TMSG1 inhibits growth and invasion of breast cancer cell in vitro through regulation of vacuolar ATPase activity. Tumour Biol. 2015;36(4):2831–44.CrossRef Mei F, You J, Liu B, Zhang M, Liu J, Zhang B, Pei F. LASS2/TMSG1 inhibits growth and invasion of breast cancer cell in vitro through regulation of vacuolar ATPase activity. Tumour Biol. 2015;36(4):2831–44.CrossRef
15.
go back to reference Imgrund S, Hartmann D, Farwanah H, Eckhardt M, Sandhoff R, Degen J, Gieselmann V, Sandhoff K, Willecke K. Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J Biol Chem. 2009;284(48):33549–60.CrossRef Imgrund S, Hartmann D, Farwanah H, Eckhardt M, Sandhoff R, Degen J, Gieselmann V, Sandhoff K, Willecke K. Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J Biol Chem. 2009;284(48):33549–60.CrossRef
16.
go back to reference Ke RH, Wang Y, Mao Y, Zhang J, Xiong J. Decreased expression of LASS2 is associated with worse prognosis in meningiomas. J Neurooncol. 2014;118(2):369–76.CrossRef Ke RH, Wang Y, Mao Y, Zhang J, Xiong J. Decreased expression of LASS2 is associated with worse prognosis in meningiomas. J Neurooncol. 2014;118(2):369–76.CrossRef
17.
go back to reference Wang H, Wang J, Zuo Y, Ding M, Yan R, Yang D, Ke C. Expression and prognostic significance of a new tumor metastasis suppressor gene LASS2 in human bladder carcinoma. Med Oncol. 2012;29(3):1921–7.CrossRef Wang H, Wang J, Zuo Y, Ding M, Yan R, Yang D, Ke C. Expression and prognostic significance of a new tumor metastasis suppressor gene LASS2 in human bladder carcinoma. Med Oncol. 2012;29(3):1921–7.CrossRef
18.
go back to reference Jin H, Wang C, Gu D, Zhang Y, Fan S, Xing S, Wang H, Ruan H, Yang C, Lv Y, Feng H, Yao M, Qin W. Liver-specific deletion of LASS2 delayed regeneration of mouse liver after partial hepatectomy. Biochem Biophys Res Commun. 2017;493(3):1176–83.CrossRef Jin H, Wang C, Gu D, Zhang Y, Fan S, Xing S, Wang H, Ruan H, Yang C, Lv Y, Feng H, Yao M, Qin W. Liver-specific deletion of LASS2 delayed regeneration of mouse liver after partial hepatectomy. Biochem Biophys Res Commun. 2017;493(3):1176–83.CrossRef
19.
go back to reference Su J, Yu W, Gong M, You J, Liu J, Zheng J. Overexpression of a novel tumor metastasis suppressor gene TMSG1/LASS2 induces apoptosis via a caspase-dependent mitochondrial pathway. J Cell Biochem. 2015;116(7):1310–7.CrossRef Su J, Yu W, Gong M, You J, Liu J, Zheng J. Overexpression of a novel tumor metastasis suppressor gene TMSG1/LASS2 induces apoptosis via a caspase-dependent mitochondrial pathway. J Cell Biochem. 2015;116(7):1310–7.CrossRef
20.
go back to reference Fan S, Niu Y, Tan N, Wu Z, Wang Y, You H, Ke R, Song J, Shen Q, Wang W, Yao G, Shu H, Lin H, Yao M, Zhang Z, Gu J, Qin W. LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump. Oncogene. 2013;32(13):1682–90.CrossRef Fan S, Niu Y, Tan N, Wu Z, Wang Y, You H, Ke R, Song J, Shen Q, Wang W, Yao G, Shu H, Lin H, Yao M, Zhang Z, Gu J, Qin W. LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump. Oncogene. 2013;32(13):1682–90.CrossRef
21.
go back to reference Turkekul K, Colpan RD, Baykul T, Ozdemir MD, Erdogan S. Esculetin inhibits the survival of human prostate cancer cells by inducing apoptosis and arresting the cell cycle. J Cancer Prev. 2018;23(1):10–7.CrossRef Turkekul K, Colpan RD, Baykul T, Ozdemir MD, Erdogan S. Esculetin inhibits the survival of human prostate cancer cells by inducing apoptosis and arresting the cell cycle. J Cancer Prev. 2018;23(1):10–7.CrossRef
22.
go back to reference Ponnusamy S, Meyers-Needham M, Senkal CE, Saddoughi SA, Sentelle D, Selvam SP, Salas A, Ogretmen B. Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance. Future Oncol. 2010;6(10):1603–24.CrossRef Ponnusamy S, Meyers-Needham M, Senkal CE, Saddoughi SA, Sentelle D, Selvam SP, Salas A, Ogretmen B. Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance. Future Oncol. 2010;6(10):1603–24.CrossRef
23.
go back to reference Rieck M, Kremser C, Jobin K, Mettke E, Kurts C, Gräler M, Willecke K, Kolanus W. Ceramide synthase 2 facilitates S1P-dependent egress of thymocytes into the circulation in mice. Eur J Immunol. 2017;47(4):677–84.CrossRef Rieck M, Kremser C, Jobin K, Mettke E, Kurts C, Gräler M, Willecke K, Kolanus W. Ceramide synthase 2 facilitates S1P-dependent egress of thymocytes into the circulation in mice. Eur J Immunol. 2017;47(4):677–84.CrossRef
24.
go back to reference Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRef Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRef
25.
go back to reference Ucker DS, Levine JS. Exploitation of apoptotic regulation in cancer. Front Immunol. 2018;9:241.CrossRef Ucker DS, Levine JS. Exploitation of apoptotic regulation in cancer. Front Immunol. 2018;9:241.CrossRef
26.
go back to reference Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;411(6835):342–8.CrossRef Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;411(6835):342–8.CrossRef
27.
go back to reference Rossi MJ, Sundararaj K, Koybasi S, Phillips MS, Szulc ZM, Bielawska A, Day TA, Obeid LM, Hannun YA, Ogretmen B. Inhibition of growth and telomerase activity by novel cationic ceramide analogs with high solubility in human head and neck squamous cell carcinoma cells. Otolaryngol Head Neck Surg. 2005;132(1):55–62.CrossRef Rossi MJ, Sundararaj K, Koybasi S, Phillips MS, Szulc ZM, Bielawska A, Day TA, Obeid LM, Hannun YA, Ogretmen B. Inhibition of growth and telomerase activity by novel cationic ceramide analogs with high solubility in human head and neck squamous cell carcinoma cells. Otolaryngol Head Neck Surg. 2005;132(1):55–62.CrossRef
28.
go back to reference Senkal CE, Ponnusamy S, Rossi MJ, Sundararaj K, Szulc Z, Bielawski J, Bielawska A, Meyer M, Cobanoglu B, Koybasi S, Sinha D, Day TA, Obeid LM, Hannun YA, Ogretmen B. Potent antitumor activity of a novel cationic pyridinium-ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitro and in vivo. J Pharmacol Exp Ther. 2006;317(3):1188–99.CrossRef Senkal CE, Ponnusamy S, Rossi MJ, Sundararaj K, Szulc Z, Bielawski J, Bielawska A, Meyer M, Cobanoglu B, Koybasi S, Sinha D, Day TA, Obeid LM, Hannun YA, Ogretmen B. Potent antitumor activity of a novel cationic pyridinium-ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitro and in vivo. J Pharmacol Exp Ther. 2006;317(3):1188–99.CrossRef
29.
go back to reference Santamaria D, Ortega S. Cyclins and CDKS in development and cancer: lessons from genetically modified mice. Front Biosci. 2006;11:1164–88.CrossRef Santamaria D, Ortega S. Cyclins and CDKS in development and cancer: lessons from genetically modified mice. Front Biosci. 2006;11:1164–88.CrossRef
30.
go back to reference Mullany LK, White P, Hanse EA, et al. Distinct proliferative and transcriptional effects of the D-type cyclins in vivo. Cell Cycle. 2008;7(14):2215–24.CrossRef Mullany LK, White P, Hanse EA, et al. Distinct proliferative and transcriptional effects of the D-type cyclins in vivo. Cell Cycle. 2008;7(14):2215–24.CrossRef
31.
go back to reference Mo J, Lin M, He B, et al. Recombinant human adenovirus-p53 improves the outcome of mid-late stage pancreatic cancer via arterial infusion. Oncol Lett. 2017;14(6):6829–32.PubMedPubMedCentral Mo J, Lin M, He B, et al. Recombinant human adenovirus-p53 improves the outcome of mid-late stage pancreatic cancer via arterial infusion. Oncol Lett. 2017;14(6):6829–32.PubMedPubMedCentral
32.
go back to reference Smits VA. EDD induces cell cycle arrest by increasing p53 levels. Cell Cycle. 2012;11(4):715–20.CrossRef Smits VA. EDD induces cell cycle arrest by increasing p53 levels. Cell Cycle. 2012;11(4):715–20.CrossRef
33.
go back to reference Kastan MB, Canman CE, Leonard CJ. P53, cell cycle control and apoptosis: implications for cancer. Cancer Metastasis Rev. 1995;14(1):3–15.CrossRef Kastan MB, Canman CE, Leonard CJ. P53, cell cycle control and apoptosis: implications for cancer. Cancer Metastasis Rev. 1995;14(1):3–15.CrossRef
34.
go back to reference Wang Y, Qiu C, Lu N, et al. FOXD1 is targeted by miR-30a-5p and miR-200a-5p and suppresses the proliferation of human ovarian carcinoma cells by promoting p21 expression in a p53-independent manner. Int J Oncol. 2018;52(6):2130–42.PubMed Wang Y, Qiu C, Lu N, et al. FOXD1 is targeted by miR-30a-5p and miR-200a-5p and suppresses the proliferation of human ovarian carcinoma cells by promoting p21 expression in a p53-independent manner. Int J Oncol. 2018;52(6):2130–42.PubMed
35.
go back to reference Huang X, Qiao Y, Zhou Y, et al. Ureaplasma spp. lipid-associated membrane proteins induce human monocyte U937 cell cycle arrest through p53-independent p21 pathway. Int J Med Microbiol. 2018;308:819–28.CrossRef Huang X, Qiao Y, Zhou Y, et al. Ureaplasma spp. lipid-associated membrane proteins induce human monocyte U937 cell cycle arrest through p53-independent p21 pathway. Int J Med Microbiol. 2018;308:819–28.CrossRef
37.
go back to reference Cerbón J, Baranda-Avila N, Falcón-Muñoz A, Camacho-Arroyo I, Cerbón M. Sphingolipid synthesis and role in uterine epithelia proliferation. Reproduction. 2018;156(2):173–83.CrossRef Cerbón J, Baranda-Avila N, Falcón-Muñoz A, Camacho-Arroyo I, Cerbón M. Sphingolipid synthesis and role in uterine epithelia proliferation. Reproduction. 2018;156(2):173–83.CrossRef
38.
go back to reference Oh E, Yun M, Kim SK, et al. Palmitate induces COX-2 expression via the sphingolipid pathway-mediated activation of NF-κB, p38, and ERK in human dermal fibroblasts. Arch Dermatol Res. 2014;306(4):339–45.CrossRef Oh E, Yun M, Kim SK, et al. Palmitate induces COX-2 expression via the sphingolipid pathway-mediated activation of NF-κB, p38, and ERK in human dermal fibroblasts. Arch Dermatol Res. 2014;306(4):339–45.CrossRef
39.
go back to reference Nicolae CM, O’Connor MJ, Constantin D, Moldovan GL. NFκB regulates p21 expression and controls DNA damage-induced leukemic differentiation. Oncogene. 2018;37:3647–56.CrossRef Nicolae CM, O’Connor MJ, Constantin D, Moldovan GL. NFκB regulates p21 expression and controls DNA damage-induced leukemic differentiation. Oncogene. 2018;37:3647–56.CrossRef
40.
go back to reference Ledoux AC, Perkins ND. NF-κB and the cell cycle. Biochem Soc Trans. 2014;42(1):76–81.CrossRef Ledoux AC, Perkins ND. NF-κB and the cell cycle. Biochem Soc Trans. 2014;42(1):76–81.CrossRef
41.
go back to reference Barré B, Perkins ND. A cell cycle regulatory network controlling NF-kappaB subunit activity and function. EMBO J. 2007;26(23):4841–55.CrossRef Barré B, Perkins ND. A cell cycle regulatory network controlling NF-kappaB subunit activity and function. EMBO J. 2007;26(23):4841–55.CrossRef
42.
go back to reference Schumm K, Rocha S, Caamano J, Perkins ND. Regulation of p53 tumour suppressor target gene expression by the p52 NF-kappaB subunit. EMBO J. 2006;25(20):4820–32.CrossRef Schumm K, Rocha S, Caamano J, Perkins ND. Regulation of p53 tumour suppressor target gene expression by the p52 NF-kappaB subunit. EMBO J. 2006;25(20):4820–32.CrossRef
Metadata
Title
Overexpression of LASS2 inhibits proliferation and causes G0/G1 cell cycle arrest in papillary thyroid cancer
Authors
Feng Zeng
Liangliang Huang
Xiaoming Cheng
Xiaoli Yang
Taolang Li
Guoli Feng
Yingqi Tang
Yan Yang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2018
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-018-0649-1

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