Lung cancer remains a major health problem in the world. Despite advances in treatment strategies the overall 5-year survival rate is only 14%. Therefore, novel therapies are needed. One attractive therapeutic approach is to identify a molecular target that is overexpressed in lung cancer and which regulates the expression of several cellular proteins that support cancer growth and metastasis. By inhibiting such a molecular target a global inhibitory effect on the expression of several proteins in a cancer cell will be produced resulting in anticancer activity. HuR, a member of the embryonic lethal abnormal vision (ELAV) protein family, is one such protein that controls the translation of numerous proteins and overexpressed in human cancers. HuR is a nucleo-cytoplasmic shuttling protein that specifically binds to mRNA that has AU rich (ARE) sites at the 3'end and transports the mRNA to the cytoplasm for protein translation. In addition to mRNA transportation, HuR plays a role in mRNA stabilization and protein translation. Studies have shown mRNA's of several growth factors, cell-cycle regulators, and transcription- regulating proteins have AREs and are bound and regulated by HuR. Additionally, HuR expression has been demonstrated to be a poor prognostic marker in patients diagnosed with cancer of the ovary, breast and colon. Although studies investigating HuR in cancer exist, the role of HuR in lung cancer, especially in non-small cell lung cancer (NSCLC), has not been investigated. In addition, very few therapeutic studies targeting HuR for cancer therapy have been investigated. On the basis of the existing literature and our own preliminary data demonstrating HuR overexpression in human lung cancer tissues we hypothesize that HuR is a novel druggable target for cancer therapy and its inhibition will downregulate multiple oncoproteins that play a role in tumor progression resulting in enhanced tumor killing. Additionally, combining HuR-targeted therapy with small molecule inhibitors will produce enhanced anticancer activity. To test our hypothesis we have identified the following specific aims:
Aim 1 : Cellular and molecular characterization of HuRSiRNA-Tf-nanoparticles (HuR-TfNPs) treatment on human lung tumor and normal cell lines in vitro.
Aim 2 : Evaluate the efficacy of HuR-TfNPs on lung metastasis in a tumor xenograft mouse model.
Aim 3 : Determine the efficacy of HuR-TfNPs treatment in combination with small molecule inhibitors in vitro and in vivo. The outcome of our studies will result in advanced preclinical testing and translation to the clinic.

Public Health Relevance

Current treatments for lung cancer have not significantly improved patient survival. Therefore there is a need for testing new therapies that are based on novel mechanisms of action, is broadly applicable, and yet minimally toxic. The goal of this project is to target HuR, an mRNA-binding protein that is overexpressed in lung cancer, using tumor-targeted nanoparticles.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Oklahoma Health Sciences Center
Schools of Medicine
Oklahoma City
United States
Zip Code
Srivastava, Akhil; Amreddy, Narsireddy; Babu, Anish et al. (2016) Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells. Sci Rep 6:38541
Muralidharan, Ranganayaki; Babu, Anish; Amreddy, Narsireddy et al. (2016) Folate receptor-targeted nanoparticle delivery of HuR-RNAi suppresses lung cancer cell proliferation and migration. J Nanobiotechnology 14:47
Panneerselvam, Janani; Srivastava, Akhil; Muralidharan, Ranganayaki et al. (2016) IL-24 modulates the high mobility group (HMG) A1/miR222 /AKT signaling in lung cancer cells. Oncotarget :
Mehta, Meghna; Basalingappa, Kanthesh; Griffith, James N et al. (2016) HuR silencing elicits oxidative stress and DNA damage and sensitizes human triple-negative breast cancer cells to radiotherapy. Oncotarget :
Amreddy, Narsireddy; Muralidharan, Ranganayaki; Babu, Anish et al. (2015) Tumor-targeted and pH-controlled delivery of doxorubicin using gold nanorods for lung cancer therapy. Int J Nanomedicine 10:6773-88
Muralidharan, R; Panneerselvam, J; Chen, A et al. (2015) HuR-targeted nanotherapy in combination with AMD3100 suppresses CXCR4 expression, cell growth, migration and invasion in lung cancer. Cancer Gene Ther 22:581-90