RASSF1C Modulates the Expression of a Stem Cell Renewal Gene, PIWIL1

Overview

Journal BMC Res Notes

Publisher Biomed Central

Specialties Biology
General Medicine

Date 2012 May 18

PMID 22591718

Citations 18

Authors

Mark E Reeves

Melissa L Baldwin

Robert Aragon

Scott Baldwin

Shin-Tai Chen

Xinmin Li

Subburaman Mohan

Yousef G Amaar

Affiliations

Soon will be listed here.

Abstract

Background: RASSF1A and RASSF1C are two major isoforms encoded by the Ras association domain family 1 (RASSF1) gene through alternative promoter selection and mRNA splicing. RASSF1A is a well established tumor suppressor gene. Unlike RASSF1A, RASSF1C appears to have growth promoting actions in lung cancer. In this article, we report on the identification of novel RASSF1C target genes in non small cell lung cancer (NSCLC).

Methods: Over-expression and siRNA techniques were used to alter RASSF1C expression in human lung cancer cells, and Affymetrix-microarray study was conducted using NCI-H1299 cells over-expressing RASSF1C to identify RASSF1C target genes.

Results: The microarray study intriguingly shows that RASSF1C modulates the expression of a number of genes that are involved in cancer development, cell growth and proliferation, cell death, and cell cycle. We have validated the expression of some target genes using qRT-PCR. We demonstrate that RASSF1C over-expression increases, and silencing of RASSF1C decreases, the expression of PIWIL1 gene in NSCLC cells using qRT-PCR, immunostaining, and Western blot analysis. We also show that RASSF1C over-expression induces phosphorylation of ERK1/2 in lung cancer cells, and inhibition of the MEK-ERK1/2 pathway suppresses the expression of PIWIL1 gene expression, suggesting that RASSF1C may exert its activities on some target genes such as PIWIL1 through the activation of the MEK-ERK1/2 pathway. Also, PIWIL1 expression is elevated in lung cancer cell lines compared to normal lung epithelial cells.

Conclusions: Taken together, our findings provide significant data to propose a model for investigating the role of RASSF1C/PIWIL1 proteins in initiation and progression of lung cancer.

Citing Articles

Mechanisms Behind the Impact of PIWI Proteins on Cancer Cells: Literature Review.

Limanowka P, Ochman B, Swietochowska E Int J Mol Sci. 2024; 25(22).

PMID: 39596284 PMC: 11594409. DOI: 10.3390/ijms252212217.

The epigenetic regulatory mechanism of PIWI/piRNAs in human cancers.

Zhang Q, Zhu Y, Cao X, Tan W, Yu J, Lu Y Mol Cancer. 2023; 22(1):45.

PMID: 36882835 PMC: 9990219. DOI: 10.1186/s12943-023-01749-3.

The Role of RASSF1C in the Tumor Microenvironment.

Amaar Y, Reeves M Curr Issues Mol Biol. 2023; 45(2):1113-1126.

PMID: 36826019 PMC: 9954811. DOI: 10.3390/cimb45020074.

The regulatory function of piRNA/PIWI complex in cancer and other human diseases: The role of DNA methylation.

Jia D, Jiang H, Zhang Y, Zhang Y, Qian L, Zhang Y Int J Biol Sci. 2022; 18(8):3358-3373.

PMID: 35637965 PMC: 9134905. DOI: 10.7150/ijbs.68221.

Critical Roles of PIWIL1 in Human Tumors: Expression, Functions, Mechanisms, and Potential Clinical Implications.

Dong P, Xiong Y, Konno Y, Ihira K, Xu D, Kobayashi N Front Cell Dev Biol. 2021; 9:656993.

PMID: 33718392 PMC: 7952444. DOI: 10.3389/fcell.2021.656993.

References

Kikuchi S, Yamada D, Fukami T, Masuda M, Sakurai-Yageta M, Williams Y . Promoter methylation of DAL-1/4.1B predicts poor prognosis in non-small cell lung cancer. Clin Cancer Res. 2005; 11(8):2954-61. DOI: 10.1158/1078-0432.CCR-04-2206. View

Tommasi S, Dammann R, Zhang Z, Wang Y, Liu L, Tsark W . Tumor susceptibility of Rassf1a knockout mice. Cancer Res. 2005; 65(1):92-8. View

Patel M, Lu L, Zander D, Sreerama L, Coco D, Moreb J . ALDH1A1 and ALDH3A1 expression in lung cancers: correlation with histologic type and potential precursors. Lung Cancer. 2007; 59(3):340-9. DOI: 10.1016/j.lungcan.2007.08.033. View

Dammann R, Takahashi T, Pfeifer G . The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas. Oncogene. 2001; 20(27):3563-7. DOI: 10.1038/sj.onc.1204469. View

Grochola L, Greither T, Taubert H, Moller P, Knippschild U, Udelnow A . The stem cell-associated Hiwi gene in human adenocarcinoma of the pancreas: expression and risk of tumour-related death. Br J Cancer. 2008; 99(7):1083-8. PMC: 2567072. DOI: 10.1038/sj.bjc.6604653. View

Li J, Wang F, Protopopov A, Malyukova A, Kashuba V, Minna J . Inactivation of RASSF1C during in vivo tumor growth identifies it as a tumor suppressor gene. Oncogene. 2004; 23(35):5941-9. DOI: 10.1038/sj.onc.1207789. View

Amaar Y, Thompson G, Linkhart T, Chen S, Baylink D, Mohan S . Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2). J Biol Chem. 2002; 277(14):12053-60. DOI: 10.1074/jbc.M110872200. View

Bunting K . ABC transporters as phenotypic markers and functional regulators of stem cells. Stem Cells. 2002; 20(1):11-20. DOI: 10.1002/stem.200011. View

Sunaga N, Miyajima K, Suzuki M, Sato M, White M, Ramirez R . Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer. Cancer Res. 2004; 64(12):4277-85. DOI: 10.1158/0008-5472.CAN-03-3941. View

10.

Vos M, Ellis C, Bell A, Birrer M, Clark G . Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis. J Biol Chem. 2000; 275(46):35669-72. DOI: 10.1074/jbc.C000463200. View

11.

Bender Kim C, Jackson E, Woolfenden A, Lawrence S, Babar I, Vogel S . Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell. 2005; 121(6):823-35. DOI: 10.1016/j.cell.2005.03.032. View

12.

Ura K, Obama K, Satoh S, Sakai Y, Nakamura Y, Furukawa Y . Enhanced RASGEF1A expression is involved in the growth and migration of intrahepatic cholangiocarcinoma. Clin Cancer Res. 2006; 12(22):6611-6. DOI: 10.1158/1078-0432.CCR-06-0783. View

13.

Amaar Y, Minera M, Hatran L, Strong D, Mohan S, Reeves M . Ras association domain family 1C protein stimulates human lung cancer cell proliferation. Am J Physiol Lung Cell Mol Physiol. 2006; 291(6):L1185-90. DOI: 10.1152/ajplung.00072.2006. View

14.

Ghaleb A, Katz J, Kaestner K, Du J, Yang V . Krüppel-like factor 4 exhibits antiapoptotic activity following gamma-radiation-induced DNA damage. Oncogene. 2006; 26(16):2365-73. PMC: 2230633. DOI: 10.1038/sj.onc.1210022. View

15.

Pelosi G, Fumagalli C, Trubia M, Sonzogni A, Rekhtman N, Maisonneuve P . Dual role of RASSF1 as a tumor suppressor and an oncogene in neuroendocrine tumors of the lung. Anticancer Res. 2010; 30(10):4269-81. View

16.

Ho M, Ng A, Lam S, Hung J . Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res. 2007; 67(10):4827-33. DOI: 10.1158/0008-5472.CAN-06-3557. View

17.

Agathanggelou A, Honorio S, Macartney D, Martinez A, Dallol A, Rader J . Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours. Oncogene. 2001; 20(12):1509-18. DOI: 10.1038/sj.onc.1204175. View

18.

Estrabaud E, Lassot I, Blot G, Le Rouzic E, Tanchou V, Quemeneur E . RASSF1C, an isoform of the tumor suppressor RASSF1A, promotes the accumulation of beta-catenin by interacting with betaTrCP. Cancer Res. 2007; 67(3):1054-61. DOI: 10.1158/0008-5472.CAN-06-2530. View

19.

Reeves M, Baldwin S, Baldwin M, Chen S, Moretz J, Aragon R . Ras-association domain family 1C protein promotes breast cancer cell migration and attenuates apoptosis. BMC Cancer. 2010; 10:562. PMC: 2965177. DOI: 10.1186/1471-2407-10-562. View

20.

Liu L, Yoon J, Dammann R, Pfeifer G . Frequent hypermethylation of the RASSF1A gene in prostate cancer. Oncogene. 2002; 21(44):6835-40. DOI: 10.1038/sj.onc.1205814. View