In Silico Characterization of Hras Pathway for Therapeutic Implications Against Cancer

Authors

  • S. Amjad Department of Biosciences, COMSATS-Institute of Information Technology, Park Road, Islamabad, Pakistan.
  • A. Naz Department of Biosciences, COMSATS-Institute of Information Technology, Park Road, Islamabad, Pakistan.
  • M. F. A. Malik Department of Biosciences, COMSATS-Institute of Information Technology, Park Road, Islamabad, Pakistan.

Abstract

Hras (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) plays a pivotal role in breast tumorigenesis. Expressional aberrations in Hras has significantly been correlated with patient’s poor overall survival. In the present study, in silico characterization of Hras to trigger downstream effectors including raf, mek, erk has been explored. Three mutational hotspots for Hras (codons12, 13, 61) have been retrieved from the literature. Promoter modelling using Proscan software revealed a promoter region lacking TATA sequence. To study the epigenetic modifications, methylation analysis of promoter lacking TATA box was done using Methylator software. Methylation is directly correlated with tumor targeting therapies as it represses expression of certain oncogenes. Five candidate sites for hypermethylation of Hras were predicted. Analysis of protein residues involved in interlocking with its downstream effector proteins was also uncovered. In addition to this, a diagnostic and therapeutic relevance of micro RNAs (miRNAs/miRs) specifically acting either as oncogene or tumor suppressors on Hras mediated pathway have been identified. Seven micro RNAs (Let-7, miR-195, miR-497, miR- 184, miR-34a, miR-34c, miR-155) found to be responsible for down regulating expression of proteins involved in rassignalling cascade while miR-372 and miR373, miR-212, miR-206/21 and miR17-92 cluster are known to elevate rassignalling pathway. Interestingly, dysregulated expression of Let-7, miR-195, miR-497, miR-184, miR-34, miR-155 co-related with poor prognosis in different cancers has also supported these in silico findings.

References

A. Jemal, F. Bray, M.M. Center, J. Ferlay, E. Ward and D.

Forman, “Global cancer statisticsâ€, CA Cancer J. Clin., vol. 61, pp.

-90, 2011.

A.F. Medarde and E. Santos, “Ras in cancer and developmental

diseasesâ€, Genes Cancer, vol. 2, pp. 344-358, 2011.

L.A. King, J. Knauf, R. Ghossein, J. Fagin, A.T. Franco, “Hras

versus Braf activation determines follicular versus papillary

thyroid cancer developmentâ€, Proceedings of 104th annual

meeting of AACR (2013), Cancer Res, vol. 73, pp. 4291,

doi:10.1158/1538-7445.AM2013-4191.

J.D. Weyandth and C.M. Counter, “Tumor suppressive effects of

wild type Hras on oncogenic Kras driven pancreatic

tumorigenesisâ€, Proceedings of AACR annual meeting (2014),

Cancer Res, vol. 74, pp. 4426, doi:10.1158/1538-7445.AM2014-

M.D. Jansson and A.H. Lund, “Micro RNA and cancerâ€, Mol.

Oncol, vol. 6,pp.590-610, 2012.

J. Winter, S. Jung, S. Keller, R.I. Gregory and S. Diederichs,

“Many roads to maturity: microRNA biogenesis pathways and

their regulationâ€, Nat. Cell. Biol, vol. 11, pp. 228-234, 2009.

M. Li, J. Li, X. Ding, M. He and S.Y. Cheng, “microRNA and

cancerâ€, AAPS. J, vol. 12,pp. 309-317, 2010.

T. Seifi, K. Ghaedi, A. Salamian, S. Tenhaei, F. Safari, Z. Hojati,

M. Tavassoli, H. Baharvand and M.H.N. Esfahani, “Amplification

of GC-rich putative mouse PeP promoter using betaine and DMSO

in ammonium sulfate polymerase chain reaction bufferâ€, Avicenna

J. Med. Biotechnol, vol. 4, pp. 206-209, 2012.

B. Dabhi and K.N. Mistry, “In silico analysis of single nucleotide

polymorphism (SNP) in human TNF-α geneâ€, Meta Gene, vol. 2,

pp. 586-595, 2012.

X. Zhou, Z. Li, Z. Dai and X. Zou, “Prediction of methylation

CpGs and their methylation degrees in human DNA sequencesâ€,

Computers in Biology and Medicine, vol. 42,pp. 408-413, 2012.

F. Bonnay, X.H. Nguyen, E.C. Berros, L. Troxler, E. Batsche, J.

Camonis, O. Takeuchi and J.M. Reichhart, N. Matt, “Akirin

specifies NF-kB selectivity of drosophila innate immune response

via chromatin remodelingâ€, The EMBO Journal, vol. 33, pp. 2349-

, 2014.

Y. Aoki, T. Niihori, H. Kawame, K. Kurosawa, H. Ohashi,

Y. Tanaka, M. Filocamo, K. Kato, Y. Suzuki, S. Kure and

Y. Matsubara, “Germline mutations in HRAS proto-oncogene

casue Costello syndromeâ€, Nat Genet, vol. 37,pp.1038-40,2005.

P.J. Roberts and C.J. Der, “Targeting the Raf-MEK-ERK mitogen

activated protein kinase cascade for the treatment of cancerâ€,

Oncogene, vol. 26, pp. 3291-3310, 2007.

V. Ceccarelli, G. Nocentini, M. Billi, S. Racanicchi, C. Riccardi,

R. Roberti, F. Grignani, L. Binglia and A. Vecchini,

“Eicosapentaenoic acid activates RAS/ERK/EBPβ pathway

thrpugh Hras intron 1 CpG island demethylation in U937 leukemia

cellsâ€, PloS One, vol. 9, pp. 1, 2014

P.M. Voorheve, C.L. Sage, M. Schrier, A.J. Gillis, H. Stoop,

R. Nagel, Y.P. Liu, J.V. Duijse, J. Drost, A. Griekspoor,

E. Zlotorynski, N. Yabuta, G.D. Vita, H. Nojima, L.H. Looijenga

and R. Agami, “ A genetic screen implicates miRNA-372 and

miRNA-373 as oncogenes in testicular germ cell tumorsâ€, Cell,

vol. 124, pp. 1169-81, 2006.

V. Olive, I. Jiang and L. He, “mir-17-92, a cluster of miRNA in the

midst of the cancer networkâ€, Intl. J. Biochem. & Cell Bio., vol.

,pp. 1348-1354, 2010.

S.B. Sharma, C.C. Lin, M.K. Farrugia, S.L. McLaughlin, E.J. Ellis,

K.M. Brundage, M.A. Salkeni and J.M. Ruppert, “MicroRNAs 206

and 21 cooperate to promote RAS-extracellular signal regulated

kinase signaling by suppressing the translation of RASA1 and

SPRED1â€, Mol. Cell. Biol.,vol. 34,pp. 4143-64, 2014.

A.E. Kerscher and F.J. Slack, “Oncomirs- MicroRNAs with a role

in cancerâ€, Nat. Rev, vol. 6, pp. 259-267, 2006.

D. Li, Y. Zhao, C. Liu, X. Chen, Y. Qi, Y. Jiang, C. Zou, X. Zhang

,S. Liu,X. Wang, D. Zhao, Q. Sun, Z. Zeng, A. Dress, M.C. Lin,

H.F. Kung, H. Rui, L. Z Liu, F. Mao, B.H Jiang and L. Lai,

“Analysis of MiR-195 and MiR-497 expression, regulation and

role in breast cancerâ€, Pub. Med., vol. 17, pp. 1722-30, 2011.

A. Kolokythas, M. Miloro and X. Zho, “Review of MicroRNA

Proposed Target Genes in Oral Cancerâ€, J. Oral &Maxillo. Res.

vol. 2, pp. 2, 2011, doi:10.5037/jomr.2011.2202.

A. Ichimura, Y. Ruike, K. Terasawa and G. Tsujimoto, “miRNAs

and regulation of cell signalingâ€, FEBS J., vol. 278, pp. 1610–

, 2011.

C.W. Chiang, Y. Huang, K.W. Leong, L.C. Chen, H.C. Chen,S.J.

Chen and C.K. Chou, “PKCα mediated induction of miR-101 in

human hepatoma HepG2 cellsâ€, Biomed Sci.,vol. 17, pp. 1186-

, 2010.

I.D. Sauthier, M.L.S. Raber, L. Capponi, C.El. Vejnar, O. Schaad,

M. Irla, Q.S. Estevez, P. Descombes, E.M. Zdobnov, H.A.Orbea

and W.Reith, “Silencing of c-fos expression by microRNA-155 is

critical for dendritic cell maturation and functionâ€, Blood, vol. 117,

pp. 4490-4500, 2010.

P. Qian, Z. Zuo, Z. Wu, P. Wang, G. Li, M. Xianyi, W. Zhang,

S. Tan, V. Pandey, Y. Yao, L. Zhao, J. Wang, Q. Wu, E. Song,

P.E. Lobie, Z. Yin and T. Zhu, “Pivotal role of reduced let-7g

expression in breast cancer invasion and metastasisâ€, Canc. Res.,

vol. 71,p. 6686, 2011.

J. Takamizawa, H. Konishi, K. Yanagisawa, S. Tomida, H. Osada ,

H.Endoh, T. Harano, Y.Yatabe, M. Nagino, Y. Nimura,

T. Mitsudomi and T. Takahash, “Reduced expression of let-7

microRNAs in human lung cancers in association with shortened

postoperative survivalâ€, Canc. Res., vol. 64, pp. 3753-3756, 2004.

P.S.H. Soon, L.J. Tacon, A.J. Gill, C.P. Bambach, M.S. Sywak,

P.R. Campbell, M.W. Yeh, S.G. Wong, R.J. Clifton-Bligh, B.G.

Robinson and S.B. Sidhu, “miR-195 and miR-483-5p identified as

predictors of poor prognosis in adrenocortical cancerâ€,Clin. Can.

Res., vol. no.15, pp. 7684, 2009.

S.Y. Ying, “Current Perspectives in microRNAs (miRNAs)â€,

Atlantic Pub. & Distr. (P) Ltd, New Delhi, 2008.

T.S. Wong, X.B. Liu, B.Y.H. Wong, R.W. Man, A.P.W. Yuen and

W.I. Wei, “Mature miR-184 as potential oncogenic microRNA of

squamous cell carcinoma of tongueâ€, Clin. Can. Res., vol. 14, pp.

-2592, 2008.

N. Kosaka, H. Iguchi and T. Ochiya, “Circulating microRNA in

body fluid: a new potential biomarker for cancer diagnosis and

prognosisâ€,Japanese Cancer Association, vol. 101, pp. 2087-2092,

A. Brendle, H. Lei, A. Brandt, R. Johansson, K. Enquist,

R. Henriksson, K. Hemminki, P. Lenner and A. Forsti,

“Polymorphisms in predicted microRNA binding sites in integrin

genes and breast cancer: ITGB4 as prognostic markerâ€, Oxford

Journals, vol. 29, pp. 1394-1399, 2008.

M. V. Iorio, M. Ferracin, C. G. Liu, A. Veronese, R. Spizzo,

S. Sabbioni, E. Magri, M. Pedriali, M. Fabbri, M. Campiglio,

S. Ménard, J.P. Palazzo, A. Rosenberg, P. Musiani, S. Volinia, I.

Nenci, G.A. Calin, P. Querzoli, M. Negrini and C.M. Croce,

“MicroRNA gene expression deregulation in human breast

cancerâ€, Cancer Res., vol. 65, pp. 7065-70, 2005.

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Published

25-05-2015

How to Cite

[1]
S. Amjad, A. Naz, and M. F. A. Malik, “In Silico Characterization of Hras Pathway for Therapeutic Implications Against Cancer”, The Nucleus, vol. 52, no. 2, pp. 50–54, May 2015.

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Vol. 52 No. 2 (2015)

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Articles