Downregulation of tumor-suppressor gene LHX6 in cancer: a systematic review

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Introduction. LIM Homeobox 6 (LHX6) encodes a LIM homeodomain transcription factor, contributes to tissue development and morphogenesis, and is mostly expressed in medial ganglionic eminence and odontogenic mesenchyme. However, it has been reported to play a role in cancer progression. This narrative review summarizes literatures that emphasize the molecular regulation of LHX6 in tumorigenesis.

Methods. In our systematic review, the PubMed database was used for the literature search using the combination of words that included “LHX6” and “cancer”. Relevant studies, including in vitro, in vivo experiments, and clinical studies, were analyzed in this review.

Results. We found evidences that LHX6 might be important in the inhibition of tumor cell proliferation, growth, invasion, and metastasis through the suppression of Wnt/β-catenin signaling pathway. Moreover, LHX6 is observed to be downregulated in certain types of cancer due to hypermethylation, thus hindering its tumor suppressing ability. In addition, hypermethylation can also be used to determine the stage of cancer development.

Conclusion. The downregulation of LHX6 expression might be responsible in promoting cancer progression. Future studies are necessary to investigate the potential of LHX6 as a novel cancer biomarker as well as its therapeutic implications towards certain types of cancer.

1. GRIGORIOU M., TUCKER AS., SHARPE PT., PACHNIS V. Expression and regulation of Lhx6 and Lhx7, a novel subfamily of LIM homeodomain encoding genes, suggests a role in mammalian head development. Development. 1998; 125(11):2063-2074.

2. ESTÉCIO MRH., YOUSSEF EM., RAHAL P., FUKUYAMA EE., GÓIS-FILHO JF., MANIGLIA JV., et al. LHX6 is a sensitive methylation marker in head and neck carcinomas. Oncogene. 2006; 25:5018-5026.

3. PERRENOUD Q., GEOFFROY H., GAUTHIER B., RANCILLAC A., ALFONSI F., KESSARIS N., et al. Characterization of type I and type II nNOS-Expressing interneurons in the barrel cortex of mouse. Front Neural Circuits. 2012; 6:36.

4. NEVES G., SHAH MM., LIODIS P., ACHIMASTOU A., DENAXA M., ROALFE G., et al. The LIM homeodomain protein Lhx6 regulates maturation of interneurons and network excitability in the mammalian cortex. Cereb Cortex. 2013; 23(8):1811–1823.

5. PASCHOU P., STYLIANOPOULOU E., KARAGIANNIDIS I., RIZZO R., TARNOK Z., WOLANCZYK T., et al. Evaluation of the LIM homeobox genes LHX6 and LHX8 as candidates for Tourette syndrome. Genes Brain Behav. 2012; 11(4):444-451.

6. ALIFRAGIS P., LIAPI A., PARNAVELAS JG. Lhx6 regulates the migration of cortical interneurons from the ventral telencephalon but does not specify their GABA phenotype. J Neurosci. 2004; 24(24):5643–5648.

7. FLANDIN P., ZHAO Y., VOGT D., JEONG J., LONG J., POTTER G., et al. Lhx6 and Lhx8 coordinately induce neuronal expression of Shh that controls the generation of interneuron progenitors. Neuron. 2011; 70(5):939–950.

8. SUSSEL L., MARIN O., KIMURA S., RUBENSTEIN JL. Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Development. 1999; 126(15):3359–3370.

9. SANDBERG M., FLANDIN P., SILBERBERG S., SU-FEHER L., PRICE JD., HU JS., et al. Transcriptional networks controlled by NKX2-1 in the development of forebrain GABAergic neurons. Neuron. 2016; 91(6):1260–1275.

10. KIM TG., YAO R., MONNELL T., CHO JH., VASUDEVAN A., KOH A., et al. Efficient specification of interneurons from human pluripotent stem cells by dorsoventral and rostrocaudal modulation. Stem Cells. 2014; 32(7):1789–1804.

11. ZHAO Y., FLANDIN P., VOGT D., BLOOD A., HERMESZ E., WESTPHAL H., et al. Ldb1 is essential for development of Nkx2.1 lineage derived GABAergic and cholinergic neurons in the telencephalon. Dev Biol. 2014; 385(1):94-106.

12. NAT R., SALTI A., SUCIU L., STRÖM S., DECHANT G. Pharmacological modulation of the hedgehog pathway differentially affects dorsal/ventral patterning in mouse and human embryonic stem cell models of telencephalic development. Stem Cells Dev. 2012; 21(7):1016–1046.

13. ZHAO Y., FLANDIN P., LONG JE., CUESTA MD., WESTPHAL H., RUBENSTEIN JL. Distinct molecular pathways for development of telencephalic interneuron subtypes revealed through analysis of Lhx6 mutants. J Comp Neurol. 2008; 510(1):79–99.

14. DU T., XU Q., OCBINA PJ., ANDERSON SA. NKX2.1 specifies cortical interneuron fate by activating Lhx6. Development. 2008; 135(8):1559-1567.

15. GEORGIEV D., GONZÁLEZ-BURGOS G., KIKUCHI M., MINABE Y., LEWIS DA., HASHIMOTO T. Selective expression of KCNS3 potassium channel α-subunit in parvalbumin-containing GABA neurons in the human prefrontal cortex. PLoS One. 2012; 7(8): e43904.

16. JAKOVCEVSKI I., MAYER N., ZECEVIC N. Multiple origins of human neocortical interneurons are supported by distinct expression of transcription factors. Cereb Cortex. 2011; 21(8):1771-1782.

17. CESARIO JM., MALT AL., DEACON LJ., SANDBERG M., VOGT D., TANG Z., et al. Lhx6 and Lhx8 promote palate development through negative regulation of a cell cycle inhibitor gene, p57Kip2. Hum Mol Genet. 2015; 24(17):5024-5039.

18. ZHAO M., GUPTA V., RAJ L., ROUSSEL M., BEI M. A network of transcription factors operates during early tooth morphogenesis. Mol Cell Biol. 2013; 33(16): 3099-3112.

19. ZHANG Z., GUTIERREZ D., LI X., BIDLACK F., CAO H., WANG J., et al. The LIM homeodomain transcription factor LHX6: a transcriptional repressor that interacts with pituitary homeobox 2 (PITX2) to regulate odontogenesis. J Biol Chem. 2013; 288(4):2485-2500.

20. DENAXA M., SHARPE PT., PACHNIS V. The LIM homeodomain transcription factors Lhx6 and Lhx7 are key regulators of mammalian dentition. Dev Biol. 2009; 33(2):324-336.

21. ARANY S., NAKATA A., KAMEDA T., KOYOTA S., UENO Y., SUGIYAMA T. Phenotype properties of a novel spontaneously immortalized odontoblast-lineage cell line. Biochem Biophys Res Commun. 2006; 342(3):718-724.

22. PRIAM F., RONCO V., LOCKER M., BOURD K., BONNEIFOIX M., DUCHÊNE T., et al. New cellular models for tracking the odontoblast phenotype. Arch Oral Biol. 2005; 50(2):271-277.

23. ZHANG Y., MORI T., TAKAKI H., TAKEUCHI M., ISEKI K., HAGINO S., et al. Comparison of the expression patterns of two LIM-homeodomain genes, Lhx6 and L3/Lhx8, in the developing palate. Orthod Craniofac Res. 2002; 5(2):65-70.

24. MOHER D., LIBERATI A., TETZLAFF J., ALTMAN DG., PRISMA GROUP. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6(7):e1000097.

25. YANG J., HAN F., LIU W., ZHANG M., HUANG Y., HAO X., et al. LHX6, an independent prognostic factor, inhibits lung adenocarcinoma progression through transcriptional silencing of β-catenin. J Cancer. 2017; 8(13):2561-2574.

26. HU Z., XIE L. LHX6 inhibits breast cancer cell proliferation and invasion via repression of the Wnt/β-catenin signaling pathway. Mol Med Rep. 2015; 12(3):4634-4639.

27. LIU W-B., JIANG X., HAN F., LI Y-H., CHEN H-Q., LIU Y., et al. LHX6 acts as a novel potential tumour suppressor with epigenetic inactivation in lung cancer. Cell Death Dis. 2013; 4(10):e882.

28. JUNG S., JEONG D., KIM J., YI L., KOO K., LEE J., et al. Epigenetic regulation of the potential tumor suppressor gene, hLHX6.1, in human cervical cancer. Int J Oncol. 2011; 38(3):859-869.

29. JUNG S., JEONG D., KIM J., YI L., KOO K., LEE J., et al. The role of hLHX6-HMR as a methylation biomarker for early diagnosis of cervical cancer. Oncol Rep. 2010; 23(6):1675-1682.

30. LIAO J., LIN J., LIN D., ZOU C., KURATA J., LIN R., HE Z., SU Y. Down-regulation of miR-214 reverses erlotinib resistance in non-small-cell lung cancer through up-regulating LHX6 expression. Sci Rep. 2017; 7(1):781.

31. LIN CJ., GRANDIS JR., CAREY TE., GOLLIN SM., WHITESIDE TL., KOCH WM., et al. Head and neck squamous cell carcinoma cell lines: established models and rationale for selection. Head and Neck. 2007; 29(2):163-188.

32. HOLLIDAY DL., SPEIRS V. Choosing the right cell line for breast cancer research. Breast Cancer Res. 2011; 13(4):215.

33. HARRIS CP., LU XY., NARAYAN G., SINGH B., MURTY VVVS., RAO PH. Comprehensive molecular cytogenetic characterization of cervical cancer cell lines. Genes Chromosome Cancer. 2003; 36(3):233-241.

34. GAZDAR AF., GIRARD L., LOCKWOOD WW., LAM WL., MINNA JD. Lung cancer cell lines as tools for biomedical discovery and research. J Natl Cancer Inst. 2010; 102(17):1310-1321.

35. NANNI P., DE GIOVANNI C., LOLLINI PL., NICOLETTI G., PRODI G. TS/A: A new metastasizing cell line from a BALB/c spontaneous mammary adenocarcinoma. Clin Exp Metastasis. 1983; 1(4):373-380.

36. GHARIB A., FAEZIZADEH Z., MESBAH-NAMIN SAR., SARAVANI R. Experimental treatment of breast cancer-bearing BALB/c mice by artemisinin and transferrin-loaded magnetic nanoliposomes. Pharmacogn Mag. 2015; 11(Suppl 1):S117-S122.

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