4.6 Article

Reduced RAR-β gene expression in Benzo(a)Pyrene induced lung cancer mice is upregulated by DOTAP lipo-ATRA treatment

Journal

GENE
Volume 668, Issue -, Pages 18-26

Publisher

ELSEVIER SCIENCE BV
DOI: 10.1016/j.gene.2018.05.051

Keywords

Benzo(a)Pyrene; Lung cancer; Lipo-ATRA; RAR-beta; RT-PCR; qPCR

Funding

  1. Department of Science and Technology - Science and Engineering Research Board (DST-SERB), Govt. of India [SB/YS/LS-252/2013]
  2. Department of Biotechnology (DBT), Govt. of India [BT/PR14632/NNT/28/824/2015]

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Molecular targeted therapy for specific genes is an emerging research. Retinoic Acid Receptor (RAR-beta) is a key tumor suppressor which is found to be lost drastically during much cancer progression. We hence, analyzed the expression level of RAR-beta gene during B(a)P induced lung cancer development in mice and studied the lung cancer targeted action of All Trans Retinoic Acid (ATRA) in DOTAP liposomal formulation. The effect of its treatment on lung cancer was determined by histopathological analysis. RAR-beta gene expression was assessed by RT-PCR and qPCR. A distinct band for RAR-beta gene (density - 0.5123 for lung and 0.5160 for liver) was observed in normal mice, whereas no visible band was observed in cancer induced group, indicating loss of RAR-beta gene expression. Both ATRA and lipo-ATRA treated groups showed detectable RAR-beta expression with relatively lesser density than the normal group. The expression was more intense in lipo-ATRA treatment (density-0.2973) compared with free ATRA treatment (density-0.1549) in lung tissues. The qPCR results also have highlighted a highly significant (p <= 0.01) variation RQ values between lipo-ATRA group (15.46 +/- 1.54) and free ATRA group (7.58 +/- 1.30) in lung tissue sample on 30th day. The mean RQ value for normal lung on 30th day was 20.86 +/- 2.58 against the cancer control. The 120th day mice also showed the similar RAR-beta expression pattern with further declined expression levels as there was no treatment given after 30 days. Interestingly, the lipo-ATRA treatment could show a highly significant (p <= 0.001) expression (12.00 +/- 2.31) when compared with free ATRA treatment (3.31 +/- 0.58) which implies that the lipo-ATRA formulation could result in sustained delivery of ATRA in target site. Histopathology of lung and liver on 120th day also revealed an effective therapeutic indication in lipo-ATRA treatment compared to free ATRA treatment due to lipo-ATRA's stealth property and it efficiently inhibited the metastasis to liver. These results revealed that the lipo-ATRA treatment has efficiently delivered ATRA into target site than free ATRA and in-turn it might have induced the expression of RAR-beta gene or prevented loss of RAR-beta gene in cancer animals.

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