We study the role of micro RNA and long non-coding RNA in cancer.
Cancer is a complex disease involving the dysregulation of many genes. The Lutz Lab studies how non-coding RNA molecules contribute to this dysregulation, particularly through inflammatory pathways. We use this knowledge to develop new treatment strategies, especially for cancers that exhibit high levels of inflammation.
The arachidonic acid pathway has important roles in tumorigenesis and inflammation
The arachidonic acid (AA) pathway is a major inflammatory signaling pathway known to have a significant role in regulating the inflammatory response and increasing cancer cell proliferation, immune evasion, and metastasis [1, 2]. The role of AA signaling in cancer has sparked recent interest in regulators of AA metabolism and the production of downstream molecules modulating immunometabolism within the TME.
The cyclooxygenase (COX) enzymes are key regulators of AA metabolism under both physiologically normal conditions and in the context of cancer. COX-2 is expressed in response to inflammation, wound healing, and other forms of cellular stress [3]. COX-2 overexpression is common for a large percentage of patients with lung cancer and has been correlated with decreased progression-free survival (PFS) in patients with stage I disease [4, 5]. Accordingly, COX-2 inhibitors complement chemotherapeutic and PD-1 immunotherapy treatments by sensitizing resistant lung cancer cells, reducing rates of metastasis and enabling immune evasion [6]. Many cancers, including NSCLC, exhibit increased PGE2 production from cancerous epithelial tissue and other cells within the TME [7].
The arachidonic acid pathway begins with the cleavage of AA from the inner leaflet of the signaling cell’s membrane by Phospholipase A2 (top). Free intracellular AA is then converted by COXs or lipoxygenases (LOXs) into parent molecules such as Prostaglandin H2, Glutathione peroxidase (GPX1), or Leukotriene A4 (middle). These parent molecules are then modified by cell-specific synthases to form a wider array of prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), all of which are potent lipid signaling molecules that will be exported to the extracellular space to bind specific transmembrane receptors on target cells (bottom).
Each receptor or receptor family is color-coded to their specific lipid signaling molecule. Long noncoding RNAs (lncRNAs) are noted in red, pharmacological inhibitors in pink, enzymes in dark blue and metabolites in black. Space-filling molecular models are diagrammed for each TX, PG, and LT with the following key: blue, carbon atoms; red, oxygen; white, hydrogen; purple, nitrogen; yellow, sulfur.
COX-2 expression is regulated by RNA-mediated mechanisms
The Lutz laboratory has previously shown that COX-2 expression is regulated by alternative polyadenylation and miRNA regulation; however, we appreciate that COX-2 regulation can occur on many levels [8, 9, 10, 11, 12, 13, 14]. Our previous work has investigated the role of miR-146a and miR-708-5p in regulating key enzymes in the AA pathway.
We are currently investigating the regulatory roles of the long non-coding RNA (lncRNA) PACER in the regulation of COX-2. We have identified several potential regulatory elements controlled by PACER expression that may be contributing to COX-2 regulations and downstream production of PGE2.
Several miRNA, including miR-146a-5p and miR-708-5p and long non-coding RNAs including PACER have regulatory roles in arachidonic acid signaling.
Lung Cancer is the Deadliest Cancer
Lung cancer remains the deadliest cancer in the United States, causing approximately 131,880 deaths in 2021 [15]. Immunotherapy treatments have greatly improved the standards of care, quality of life, and survival for many patients; however, dysregulation of inflammation in lung tumors make treatment more difficult for certain patients.
Lung tumor cells manipulate your body's ability to regulate inflammation. Immune cells can also impact inflammation in and around the tumor. The tumor cells and surrounding immune cells form the tumor environment. Genes expressed in the tumor environment shape how cancer develops in each patient.
Despite the significant efforts made to understand how inflammation impacts the development and progression of lung tumors, many unanswered questions remain. The broad research goal of the Lutz laboratory is to help answer these questions and develop new RNA-based strategies to regulate inflammation in lung cancer.
Adapted from The 2020, American Cancer Society, Inc., Surveillance Research
Reference Links
1. Monteleone, N.J. and C.S. Lutz, miR-708-5p targets oncogenic prostaglandin E2 production to suppress a pro-tumorigenic phenotype in lung cancer cells. Oncotarget, 2020. 11(26): p. 2464-2483.
2. Davies, G., et al., Cyclooxygenase-2 (COX-2), aromatase and breast cancer: a possible role for COX-2 inhibitors in breast cancer chemoprevention. Ann Oncol, 2002. 13(5): p. 669-78.
3. Hla, T., et al., Cyclooxygenase-1 and -2 isoenzymes. Int J Biochem Cell Biol, 1999. 31(5): p. 551-7.
4. Achiwa, H., et al., Prognostic significance of elevated cyclooxygenase 2 expression in primary, resected lung adenocarcinomas. Clin Cancer Res, 1999. 5(5): p. 1001-5.
5. Zhang, W., et al., Comparison of the benefits of celecoxib combined with anticancer therapy in advanced non-small cell lung cancer: A meta-analysis. J Cancer, 2020. 11(7): p. 1816-1827.
6. Ching, M.M., J. Reader, and A.M. Fulton, Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy. Front Pharmacol, 2020. 11: p. 819.
7. Wang, D. and R.N. Dubois, Eicosanoids and cancer. Nat Rev Cancer, 2010. 10(3): p. 181-93.
8. Lutz, C.S. and A.L. Cornett, Regulation of genes in the arachidonic acid metabolic pathway by RNA processing and RNA-mediated mechanisms. Wiley Interdiscip Rev RNA, 2013. 4(5): p. 593-605.
9. Cornett, A.L. and C.S. Lutz, Regulation of COX-2 expression by miR-146a in lung cancer cells. RNA, 2014. 20(9): p. 1419-30.
10. Monteleone, N.J. and C.S. Lutz, miR-708-5p enhances erlotinib/paclitaxel efficacy and overcomes chemoresistance in lung cancer cells. Oncotarget, 2020. 11(51): p. 4699-4721.
11. Dixon, D.A., Regulation of COX-2 expression in human cancers. Prog Exp Tumor Res, 2003. 37: p. 52-71.
12. Dixon, D.A., et al., Post-transcriptional control of cyclooxygenase-2 gene expression: the role of the 3′-untranslated region. Journal of Biological Chemistry, 2000. 275(16): p. 11750-11757.
13. Young, L.E., et al., The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2. Mol Cancer Res, 2012. 10(1): p. 167-80.
14. Hall-Pogar, T., et al., Specific trans-acting proteins interact with auxiliary RNA polyadenylation elements in the COX-2 3'-UTR. RNA, 2007. 13(7): p. 1103-15.
15. The American Cancer Society Facts & Figures 2020. p. 10.