Pathology & Oncology Research

, Volume 24, Issue 2, pp 207–214 | Cite as

Molecular Alterations and Expression Dynamics of LATS1 and LATS2 Genes in Non-Small-Cell Lung Carcinoma

  • Showkat A. Malik
  • Mosin S. Khan
  • Majeed Dar
  • Mahboob Ul Hussain
  • Mohammad A. Shah
  • Sheikh M. Shafi
  • Syed Mudassar
Original Article


Large tumor suppressor (LATS) is an important member of the Hippo pathway which can regulate organ size and cell proliferation. However, very little is known about the expression and clinical significance of LATS in lung cancer especially from this part of the world. We elucidated the frequency of LATS1 &LATS2 promoter hypermethylation (by methylation-specific PCR) and expression (by real-time PCR) in sixty nine (n = 69) Non-Small Cell Lung Cancer (NSCLC) patients and their corresponding normal lung tissue samples. We found promoter hypermethylation frequencies of LATS1 & LATS1to be 66.66% (46/69) and 71% (49/69) in NSCLC tissues. Decreased LATS1 & LATS2 mRNA expression was found in 55% and 66.66% of NSCLC patients. The LATS1 mRNA expression was significantly higher in normal lung tissues. Also, the mRNA levels of LATS1 and LATS2 NSCLC tissues with hypermethylation were significantly lower. Multivariable analysis confirmed that LATS1 under expression increased the hazard of death after adjusting for other clinicopathological factors. Importantly, the loss of LATS1 mRNA expression was associated with overall short survival. LATS1 is an independent prognostic factor and may play an important role in NSCLC progression and may serve as a novel therapeutic target of NSCLC.


Lung cancer Survival Hazard ratio Non-small cell lung cancer LATS1 LATS2 



The authors gratefully acknowledge the Technical Staff of the operation theater of Department of CVTS. This study was supported by Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Soura, Srinagar, Kashmir 190011, India (Grant no# No.SIMS/ACAD/14-786).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there is no conflict of interest.


  1. 1.
    Travis WD (2011) Pathology of lung cancer. Clin Chest Med 32:669–692CrossRefPubMedGoogle Scholar
  2. 2.
    World Health Organization (2012) Cancer (
  3. 3.
    Travis LB, Gospodarowicz M, Curtis RE et al (2002) Lung cancer following chemotherapy and radiotherapy for Hodgkin’s disease. J Natl Cancer Inst 94:182–192CrossRefPubMedGoogle Scholar
  4. 4.
    O'Mahony D, Kummar S, Gutierrez ME (2005) Non-small-cell lung cancer vaccine therapy: a concise review. J Clin Oncol 23:9022–9028CrossRefPubMedGoogle Scholar
  5. 5.
    Nanda KA (2001) Consolidated report of the population based cancer registries, incidence & distribution of cancer, 1990–1996. Indian Council of Medical research, National Cancer Registry Program, New DelhiGoogle Scholar
  6. 6.
    Pandith AA, Siddiqi MA (2012) Burden of cancers in the valley of Kashmir: 5Year epidemiological study reveals a different scenario. Tumor Biol 33:1629–1637CrossRefGoogle Scholar
  7. 7.
    Zheng T, Wang J, Jiang H, Liu L (2011) Hippo signaling in oval cells and hepato-carcinogenesis. Cancer Lett 302:91–99CrossRefPubMedGoogle Scholar
  8. 8.
    Halder G, Johnson RL (2011) Development 138:9–22Google Scholar
  9. 9.
    Xia H, Qi H, Li Y, Pei J, Barton J, Blackstad M, Xu T, Tao W (2002) LATS1 tumor suppressor regulates G2/M transition and apoptosis. Oncogene 21:1233–1241CrossRefPubMedGoogle Scholar
  10. 10.
    Tao W, Zhang S, Turenchalk GS et al (1999) Human homologue of the Drosophila melanogaster LATS tumour suppressor modulates CDC2 activity. Nat Genet 21:177–181CrossRefPubMedGoogle Scholar
  11. 11.
    Avruch J, Zhou D, Bardeesy N (2012) YAP oncogene overexpression supercharges colon cancer proliferation. Cell Cycle 11:1090–1096CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hisaoka M, Tanaka A, Hashimoto H (2002) Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma. Lab Investig 82:1427–1435CrossRefPubMedGoogle Scholar
  13. 13.
    Matallanas D, Romano D et al (2007) RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. Mol Cell 27:962–975CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    McPherson JP, Tamblyn L, Elia A et al (2004) LATS2/Kpm is required for embryonic development, proliferation control and genomic integrity. EMBO J 23:3677–3688CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Yabuta N, Okada N, Ito A et al (2007) Lats2 is an essential mitotic regulator required for the coordination of cell division. J Biol Chem 282:19259–19271CrossRefPubMedGoogle Scholar
  16. 16.
    Ke H, Pei J, Ni Z, Xia H, Qi H, Woods T, Kelekar A, Tao W (2004) Putative tumor suppressor LATS2 induces apoptosis through down-regulation of Bcl-2 and Bcl-x(L). Exp Cell Res 298:329–338CrossRefPubMedGoogle Scholar
  17. 17.
    Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G, Lu D (2006) Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci Res 56:450–458CrossRefPubMedGoogle Scholar
  18. 18.
    Jiménez-Velasco A, Román-Gómez J et al (2005) Down-regulation of the large tumor suppressor 2 (LATS/KPM) gene is associated with poor prognosis in acute lymphoblastic leukemia. Leukemia 19:2347–2350CrossRefPubMedGoogle Scholar
  19. 19.
    Sasaki H, Hikosaka Y, Kawano O, Yano M, Fujii Y (2010) Hypermethylation of thelargetumor suppressor genes in Japanese lung cancer. Oncol Lett 1:303–307CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T, Tamaki Y, Noguchi S (2005) Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin Cancer Res 11:1380–1385CrossRefPubMedGoogle Scholar
  21. 21.
    Bao Y, Hata Y, Ikeda M, Withanage K (2011) Mammalian hippo pathway: from development to cancer and beyond. J Biochem 149:361–379CrossRefPubMedGoogle Scholar
  22. 22.
    Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl Acad Sci USA 93:9821–9826CrossRefGoogle Scholar
  23. 23.
    Steinmann K, Sandner A, Schagdarsurengin U, Dammann RH (2009) Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma. Oncol Rep 22:1519–1526PubMedGoogle Scholar
  24. 24.
    Xu-Yng L, Xiu-Peng Z, Jun-Hua W, Xue-Shan Q, En-Hua W (2014) Expression of LATS1 contribute to good prognosis and can negatively regulate YAP oncoprotein in non-small cell lung cancer. Tumor Biol 35:6435–6443CrossRefGoogle Scholar
  25. 25.
    Tianhai J, Dan L, Wei S, Wensheng Y, Haiqiao W, Xiuwu B (2012) Decreased exoression of LATS1 is correlated with the progression and prognosis of glioma. J Exp Clin Cancer Res 31:67–75CrossRefGoogle Scholar
  26. 26.
    Wierzbicki PM, Adrych K, Kartanowicz D et al (2013) Underexpression of LATS1 TSG in colorectal cancer is associated with promoter hypermethylation. World J Gastroenterol 19:4363–4373CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhou G-X, Xiao-Yu L, Qi Z et al (2013) Effects of the hippo signaling pathway in human gastric cancer. Asian Pac J Cancer Prev 14:5199–5205CrossRefPubMedGoogle Scholar
  28. 28.
    Xia H, Qi H, Li Y, Pei J, Barton J, Blackstad M, Xu T, Tao W (2002) LATS1 tumor suppressor regulates G2/M transition and apoptosis. Oncogene 21:1233–1241CrossRefPubMedGoogle Scholar
  29. 29.
    Yang X, Li DM, Chen W, Xu T (2001) Human homologue of Drosophila LATS, negatively regulate growth by inducing G(2)M arrest or apoptosis. Oncogene 20:6516–6523CrossRefPubMedGoogle Scholar
  30. 30.
    Liang K, Zhou G, Zhang Q, Li J, Zhang C (2014) Expresssion of hippo pathway in colorectal cancer. Saudi J Gastroenterol 20:188–194CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Luo SY, Sit KY, Sihoe AD, Suen WS et al (2014) Abberant large tumor suppressor 2 (LATS2) gene expression correlates with EGFR mutation and survival in lung adenocarcinomas. Lung Cancer 85:282–292CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Yu T, Bachman J, Lai ZC (2013) Evidence for a tumor suppressor role forthe large tumor suppressor genes LATS1 and LATS2 in humancancer. Genetics 195:1193–1196CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ishizaki K, Fujimoto J, Kumimoto H et al (2002) Frequent polymorphic changes but rare tumor specific mutations of the LATS2 gene on 13q11-12 in esophageal squamous cell carcinoma. Int J Oncol 21:1053–1057PubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2017

Authors and Affiliations

  • Showkat A. Malik
    • 1
  • Mosin S. Khan
    • 1
  • Majeed Dar
    • 2
  • Mahboob Ul Hussain
    • 3
  • Mohammad A. Shah
    • 1
  • Sheikh M. Shafi
    • 1
  • Syed Mudassar
    • 1
  1. 1.Department of Clinical BiochemistrySher-I-Kashmir Institute of Medical SciencesSrinagarIndia
  2. 2.Department of Cardiovascular and Thoracic SurgerySher-I-Kashmir Institute of Medical SciencesSrinagarIndia
  3. 3.Department of BiotechnologyUniversity of KashmirSrinagarIndia

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