Am J Cancer Res 2013;3(5):465-477

Original Article
Down-regulation of miR-221 inhibits proliferation of pancreatic cancer cells
through up-regulation of PTEN, p27kip1, p57kip2, and PUMA

Shaan Sarkar, Hala Dubaybo, Shadan Ali, Priscila Goncalves, Sri Lakshmi Kollepara, Seema Sethi, Philip A Philip, Yiwei Li

Departments of Pathology, Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine,
Detroit, MI, USA

Received September 24, 2013; Accepted October 20, 2013; Epub November 1, 2013; Published November 15, 2013

Abstract: Pancreatic cancer is the fourth leading cause of cancer related death in the US and exhibits aggressive features with
short survival rate and high mortality. Therefore, it is important to understand the molecular mechanism(s) involved in the
aggressive growth of pancreatic cancers, and further design novel targeted therapies for its treatment with better treatment
outcome. In the present study, we found that the expression of miR-221 was significantly up-regulated in pancreatic cancer cell
lines and tumor tissues compared to normal pancreatic duct epithelial cells and normal pancreas tissues. Moreover, we found
that the pancreatic cancer patients with high miR-221 expression had a relatively shorter survival compared to those with lower
expression, suggesting that miR-221 could be an oncogenic miRNA and a prognostic factor for poor survival of patients.
Interestingly, transfection of miR-221 inhibitor suppressed the proliferative capacity of pancreatic cancer cells with concomitant
up-regulation of PTEN, p27kip1, p57kip2, and PUMA, which are the tumor suppressors and the predicted targets of miR-221.
Most importantly, we found that the treatment of pancreatic cancer cells with isoflavone mixture (G2535), formulated 3,3’-
diindolylmethane (BR-DIM), or synthetic curcumin analogue (CDF) could down-regulate the expression of miR-221 and
consequently up-regulate the expression of PTEN, p27kip1, p57kip2, and PUMA, leading to the inhibition of cell proliferation and
migration of MiaPaCa-2 and Panc-1 cells. These results provide experimental evidence in support of the oncogenic role of miR-
221 and also demonstrate the role of isoflavone, BR-DIM, and CDF as potential non-toxic agents that are capable of down-
regulation of miR-221. Therefore, these agents combined with conventional chemotherapeutics could be useful in designing
novel targeted therapeutic strategy for the treatment of pancreatic cancer for which there is no curative therapy. (ajcr0000231).

Keywords: miR-221, proliferation, pancreatic cancer, isoflavone, DIM, CDF

Address correspondence to: Yiwei Li, Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State
University School of Medicine, 715 Hudson Webber Cancer Research Center, 4100 John R, Detroit, MI 48201, USA. Tel: 313-576-
8318; Fax: 313-576-8389; E-mail:
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American Journal of Cancer Research
ISSN: 2156-6976