Despite progress in recent years, pancreatic cancer still remains a major clinical challenge. Its incidence and mortality rates have been on consistent rise, thus underscoring the critical need for novel diagnostic, prognostic and therapeutic tools for its effective management. Recent studies have demonstrated that microRNAs (miRNAs/miRs) are deregulated in a variety of malignancies, including pancreatic cancer, and play a significant role in the initiation, progression and metastasis. Furthermore, their vital involvement in the therapeutic resistance of cancer has also been established. Hence, there has been enormous interest worldwide in investigating the roles of miRNAs in pancreatic cancer pathogenesis and exploiting their utility for clinical benefit. In this review, we summarize current knowledge on the role of miRNAs in pancreatic cancer and discuss their potential use as diagnostic and prognostic biomarkers, and as novel targets for development of effective therapeutic strategies.

MicroRNAs (miRNAs) are small, endogenous noncoding RNAs that regulate a variety of biological processes such as differentiation, development, and survival. Recent studies suggest that miRNAs are dysregulated in cancer and play critical roles in cancer initiation, progression, and chemoresistance. Therefore, exploitation of miRNAs as targets for cancer prevention and therapy could be a promising approach. Extensive evidence suggests that many naturally occurring phytochemicals regulate the expression of numerous miRNAs involved in the pathobiology of cancer. Therefore, an understanding of the regulation of miRNAs by phytochemicals in cancer, their underlying molecular mechanisms, and functional consequences on tumor pathophysiology may be useful in formulating novel strategies to combat this devastating disease. These aspects are discussed in this review paper with an objective of highlighting the significance of these observations from the translational standpoint.

The poor clinical outcome of pancreatic cancer (PC) is largely attributed to its aggressive nature and refractoriness to currently available therapeutic modalities. We previously reported antitumor efficacy of honokiol (HNK), a phytochemical isolated from various parts of Magnolia plant, against PC cells in short-term in vitro growth assays. Here, we report that HNK reduces plating efficiency and anchorage-independent growth of PC cells and suppresses their migration and invasiveness. Furthermore, significant inhibition of pancreatic tumor growth by HNK is observed in orthotopic mouse model along with complete-blockage of distant metastases. Histological examination suggests reduced desmoplasia in tumors from HNK-treated mice, later confirmed by immunohistochemical analyses of myofibroblast and extracellular matrix marker proteins (α-SMA and collagen I, respectively). At the molecular level, HNK treatment leads to decreased expression of sonic hedgehog (SHH) and CXCR4, two established mediators of bidirectional tumor-stromal cross-talk, both in vitro and in vivo. We also show that the conditioned media (CM) from HNK-treated PC cells have little growth-inducing effect on pancreatic stellate cells (PSCs) that could be regained by the addition of exogenous recombinant SHH. Moreover, pretreatment of CM of vehicle-treated PC cells with SHH-neutralizing antibody abolishes their growth-inducing potential on PSCs. Likewise, HNK-treated PC cells respond poorly to CM from PSCs due to decreased CXCR4 expression. Lastly, we show that the transfection of PC cells with constitutively active IKKβ mutant reverses the suppressive effect of HNK on nuclear factorkappaB activation and partially restores CXCR4 and SHH expression. Taken together, these findings suggest that HNK interferes with tumor-stromal cross-talk via downregulation of CXCR4 and SHH and decreases pancreatic tumor growth and metastasis.

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Pancreatic cancer (PC) is the fourth leading cause of cancer-related death in the United States with a five year survival rate at just 6.0%. Its poor clinical outcome is largely attributed to its aggressive and metastatic nature as well as refractoriness to currently available therapeutic modalities. Hence, there is a critical need to develop novel and more effective treatments for this malignancy. We previously reported that honokiol (HNK), a phytochemical isolated from the leaves and bark of Magnolia grandiflora, suppresses the growth of PC cells. Moreover, HNK sensitized PC cells to gemcitabine by preventing its activation of NF-kB pathway. Here, we have further analyzed the effects of HNK on clonogenicity, stemness, tumorigenicity and metastasis by performing in vitro and in vivo functional assays. Furthermore, we have conducted biochemical, histological and immunohistochemical analyses on vehicle and HNK-treated tumor cells and xenografts to examine the mechanism of action and molecular targets of HNK. We report that HNK treatment reduces the clonogenicity and stemness of PC cells as well as limits their capability to migrate and invade through the extracellular matrix. Our animal studies demonstrate that HNK significantly impedes the growth of pancreatic tumors and reduces the incidence as well as extent of metastases. Histological and immunohistochemical analyses suggest a decrease in desmoplasia, which is a key feature of pancreatic adenocarcinomas, acting as a physical barrier for drug delivery. At the molecular level, we have observed that HNK decreases the expression of hedgehog pathway through suppression of SHH production in PC cells. Further, we demonstrate a suppression of CXCR4 (a receptor for stromal cell derived chemokine, CXCL12) after treatment with HNK in a dose- and time-dependent manner. This is highly significant considering the known functions of SHH/CXCR4 signaling axes in growth, invasion, metastasis and therapeutic resistance of pancreatic tumor cells. Using transient transfection of constitutively active IKKB; mutant (pCMV-IKKB; S177E S181E) to neutralize the suppressive effect of HNK on NF-kB activation, we reveal its partial role in downregulation of CXCR4 and SHH expression. Together, our findings suggest that HNK likely impacts multiple molecular pathways to confer its anti-tumor activity and thus support its potential utility as a novel agent for PC therapy and/or prevention. Citation Format: Courey A. Averett, Arun Bhardwaj, Sumit Arora, Sanjeev Srivastava, Seema Singh, JE Carter, Ajay P. Singh. Honokiol attenuates stemness, growth and metastasis of pancreatic tumor cells: A novel natural agent for therapy and prevention. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B02.