Cervical cancer is the second most frequently diagnosed cancer and the second leading cause of cancer related deaths in women worldwide. American Indian (AI) women living on the Northern Plains have a greater incidence of cervical cancer and suffer from a higher mortality rate. Our recent studies have shown that AI women have more than twice the incidence of HPV infection and that HPV positive AI women have a two times higher likelihood of having abnormal PAP tests than HPV positive Caucasian women;suggesting underlying causes which increase HPV pathology. One potential cofactor may be smoke exposure and its effects on the host immune response and HPV oncogenesis. Our data indicate that 4 times more AI women smoke as compared to Caucasian women and the majority of HPV positive AI women smoke. While smoking is a recognized risk factor for cervical cancer, the molecular interactions between HPV and smoke compounds are unknown. Our laboratory has recently shown that smoke carcinogen Benzo[a]Pyrene (BaP) increases the expression of HPV oncoproteins, suggesting a direct molecular link between HPV infection and exposure to smoke. We have also identified that curcumin, a natural anti-cancer compound, effectively inhibits the expression of HPV oncoproteins. Based on this compelling evidence, we hypothesize that exposure to tobacco smoke synergizes with HPV infection and increases the incidence and severity of cervical cancer in American Indian women by increasing the expression of HPV oncoproteins (E6/E7) and modulating cellular/humoral immune responses. Additionally, we hypothesize that curcumin or nanocurcumin may be effective methods for the repression of HPV infection in AI women. We propose to 1) investigate novel mechanisms of synergy between HPV infection, BaP and the development of cervical cancer, 2) evaluate the efficacy of curcumin/nanocurcumin to suppress HPV oncogene expression in preclinical and clinical settings, and 3) to investigate the effect of smoke exposure on cervical immune responses. The results of this study will provide information regarding underlying etiological factors that are responsible for cervical cancer health disparity in AI women and will ultimately reduce the burden of cervical cancer.

Public Health Relevance

Project Narrative American Indian (AI) women living in the Northern Plains have a greater incidence of cervical cancer and suffer from a higher mortality rate. This study will provide information regarding etiological factors that are responsible for cervical cancer health disparity in AI women, ultimately reducing the burden of cervical cancer in AI women and serving as a platform to reduce cervical cancer in other underserved populations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA162106-01A1
Application #
8287944
Study Section
Special Emphasis Panel (ZRG1-OBT-A (55))
Program Officer
Daschner, Phillip J
Project Start
2012-06-21
Project End
2013-05-31
Budget Start
2012-06-21
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$327,850
Indirect Cost
$120,350
Name
Sanford Research/Usd
Department
Type
DUNS #
050113252
City
Sioux Falls
State
SD
Country
United States
Zip Code
57104
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Setua, Saini; Khan, Sheema; Yallapu, Murali M et al. (2016) Restitution of Tumor Suppressor MicroRNA-145 Using Magnetic Nanoformulation for Pancreatic Cancer Therapy. J Gastrointest Surg :
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Yallapu, Murali M; Nagesh, Prashanth K Bhusetty; Jaggi, Meena et al. (2015) Therapeutic Applications of Curcumin Nanoformulations. AAPS J 17:1341-56

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