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General Commentary ARTICLE

Front. Oncol., 16 October 2012 | https://doi.org/10.3389/fonc.2012.00134

Skp2 and its emerging role in the pathogenesis of systemic malignancies besides breast carcinomas

  • Mechanicsville, VA, USA

A commentary on

Skp2 is a promising therapeutic target in breast cancer
by Wang, Z., Fukushima, H., Inuzuka, H., Wan, L., Liu, P., Gao, D., Sarkar, F. H., and Wei, W. (2012). Front. Oncol. 1:57. doi: 10.3389/fonc.2011.00057

The recent article by Wang et al. (2012a) was highly interesting. Interestingly, recent data suggests that Skp2 expression may play a significant role in the etio-pathogenesis of a number of systemic malignancies besides breast carcinomas.

For instance, the expression of Skp2 in prostate cancers is decreased by androgens and is mediated via pathways that are dependent on p107 as well as pathways that are independent of p107 (Jiang et al., 2012). Similarly, accentuated Skp2 expression in prostate carcinomas may result in the loss of the tumor suppressor gene BRCA2 (Arbini et al., 2011). Thus Skp2 may be a potential therapeutic target for the management of prostate malignancies (Wang et al., 2012b).

Similarly, the prognosis on ovarian cancers is influenced by Skp2. In fact, Skp2 expression by ovarian carcinomas is significantly associated with not only tumor stage but also lymph node metastasis (Lu et al., 2012). Skp2 also is as a receptor for dihydro-testosterone. As a result dihydro-testosterone regulates p27 degradation in ovarian carcinomas (Shi et al., 2011).

Similarly, resistance toward tumor necrosis factor related apoptosis inducing ligand (TRAIL) induced apoptosis in gastrointestinal malignancies especially pancreatic carcinomas is mediated by Skp2 (Schuler et al., 2011). This makes Skp2 a potential onco-target in the management of pancreatic malignancies. A similar association is seen in salivary carcinomas. Accentuated Skp2 expression is associated with decreased survival probability rates and a worse clinical outcome (Ben-Izhak et al., 2009).

Similarly, Skp2 has a role to play in the etio-pathogenesis of lung carcinomas. Non-small cell lung cancers typically demonstrated increased Skp2 expression. It promotes cellular invasion in pulmonary malignancies by up regulating matrix metalloproteinase-9 (MMP-9) as well as matrix metalloproteinase-2 (MMP-2; Hung et al., 2010). Not surprisingly, agents such as tubocapsanolide A attenuate the expression of Skp2 and thereby have a negative effect on cellular proliferation in pulmonary malignancies (Chang et al., 2007). Interestingly, WIF1 causes inhibition of proliferation in tumors such as bladder carcinomas by modulating Skp2 function besides regulating the expression of c-myc (Tang et al., 2009).

Clearly, Skp2 is involved in the pathogenesis of a number of systemic malignancies. It is a potential onco-target and further studies are needed to further identify compounds that can target Skp2 expression.

References

Arbini, A. A., Greco, M., Yao, J. L., Bourne, P., Marra, E., Hsieh, J. T., et al. (2011). Skp2 overexpression is associated with loss of BRCA2 protein in human prostate cancer. Am. J. Pathol. 178, 2367–2376.

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Ben-Izhak, O., Akrish, S., Gan, S., and Nagler, R. M. (2009). Skp2 and salivary cancer. Cancer Biol. Ther. 8, 153–158.

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Chang, H. C., Chang, F. R., Wang, Y. C., Pan, M. R., Hung, W. C., and Wu, Y. C. (2007). A bioactive with anolide tubocapsanolide A inhibits proliferation of human lung cancer cells via repressing Skp2 expression. Mol. Cancer Ther. 6, 1572–1578.

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Hung, W. C., Tseng, W. L., Shiea, J., and Chang, H. C. (2010). Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells. Cancer Lett. 288, 156–161.

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Jiang, J., Pan, Y., Regan, K. M., Wu, C., Zhang, X., Tindall, D. J., et al. (2012). Androgens repress expression of the F-box protein Skp2 via p107 dependent and independent mechanisms in LNCaP prostate cancer cells. Prostate 72, 225–232.

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Lu, M., Zhao, Y., Xu, F., Wang, Y., Xiang, J., and Chen, D. (2012). The expression and prognosis of FOXO3a and Skp2 in human ovarian cancer. Med. Oncol. PMID:22714061. [Epub ahead of print].

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Schuler, S., Diersch, S., Hamacher, R., Schmid, R. M., Saur, D., and Schneider, G. (2011). SKP2 confers resistance of pancreatic cancer cells towards TRAIL-induced apoptosis. Int. J. Oncol. 38, 219–225.

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Shi, P., Zhang, Y., Tong, X., Yang, Y., and Shao, Z. (2011). Dihydrotestosterone induces p27 degradation via direct binding with SKP2 in ovarian and breast cancer. Int. J. Mol. Med. 28, 109–114.

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Tang, Y., Simoneau, A. R., Liao, W. X., Yi, G., Hope, C., Liu, F., et al. (2009). WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells. Mol. Cancer Ther. 8, 458–468.

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Wang, Z., Fukushima, H., Inuzuka, H., Wan, L., Liu, P., Gao, D., et al. (2012a). Skp2 is a promising therapeutic target in breast cancer. Front. Oncol. 1:57. doi: 10.3389/fonc.2011.00057

CrossRef Full Text

Wang, Z., Gao, D., Fukushima, H., Inuzuka, H., Liu, P., Wan, L., et al. (2012b). Skp2: a novel potential therapeutic target for prostate cancer. Biochim. Biophys. Acta 1825, 11–17.

Citation: Kapoor S (2012) Skp2 and its emerging role in the pathogenesis of systemic malignancies besides breast carcinomas. Front. Oncol. 2:134. doi: 10.3389/fonc.2012.00134

Received: 31 August 2012; Accepted: 19 September 2012;
Published online: 16 October 2012.

Edited by:

Tiziana Venesio, Istituto per la Ricerca e la Cura del Cancro, Italy

Copyright: © 2012 Kapoor. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: shailendrakapoor@yahoo.com