Pilot Project 2: Nrf2 Activation in Esophageal Squamous Cell Carcinogenesis in Vivo

Partnership

Dr. Major is well established in his research work on the biochemical mechanisms of Nrf2 signaling in cancer development. He has published multiple manuscripts in this area. Dr. Chen is well established in esophageal cancer research. This partnership pilot project brings two groups together to understand the molecular mechanisms of Nrf2 activation in esophageal squamous cell carcinogenesis.

Cancer Disparity

Esophageal cancer ranks the eighth most common and the sixth most deadly type of cancer worldwide. There are mainly two histological types of esophageal cancer, squamous cell carcinoma (ESCC) and esophageal adenocarcinoma, each having a distinct etiology. Low income, moderate/heavy alcohol intake, tobacco use and infrequent consumption of raw fruits and vegetables account for almost all cases of ESCC and for the excess incidence among African American men. Recent epidemiological studies in the US have shown that during 1977- 2005, more than 27,000 primary invasive esophageal cancers were diagnosed among Caucasian Americans and African Americans according to SEER 9 registries. ESCC accounts for 87% of all esophageal cancer in African Americans, but only for 45% in Caucasian Americans. The ESCC rate among African American men was ~5 times that among Caucasian American men (13.6 vs 2.7 per 100,000 person-years, respectively), while the rate among African American women was ~3 times that among Caucasian women (4.1 vs 1.2, respectively). Although the ESCC rate has been slightly declining in this country, disparity between African Americans and Caucasian Americans is still quite striking in the past three decades. Racial disparity of ESCC is obvious not only in cancer incidence, but also in cancer survival. Cumulative survival data have shown that African Americans are significantly worse than Caucasian Americans in surviving ESCC despite controlling for confound variables. Therefore, it is important to better understand molecular mechanisms of ESCC and develop targeted therapy for this deadly disease in order to reduce racial disparity.

Abstract

Esophageal squamous cell carcinoma (ESCC) predominantly affects African Americans rather than Caucasian Americans at a ratio of about 4:1. African American patients with ESCC have much worse prognosis than their Caucasian counterparts. Therefore, it is important to understand better the molecular mechanisms of ESCC and develop targeted therapy for this deadly disease in order to reduce racial disparity. Recent NextGen sequencing studies have identified multiple driver mutations in human ESCC among which Nrf2 and Keap1 mutations are known to activate Nrf2 signaling. However, the molecular mechanisms of Nrf2-associated carcinogenesis have not been clearly understood particularly in vivo. Based on our preliminary data, we hypothesize that Nrf2 activation induces esophageal hyperproliferation and hyperkeratosis through metabolic reprogramming.

Using the Keap1-/- mouse model of esophageal hyperproliferation and hyperkeratosis, we plan to test our hypothesis with two specific aims: (1) To examine whether Nrf2 activation in Keap1-/- esophagus activates metabolic reprogramming through transcriptional regulation of energy metabolism genes, and (2)To test whether genetic or chemical inhibition of metabolic reprogramming may suppress esophageal phenotype in Keap1-/- mice.

This Pilot Project is aimed to understand the carcinogenic mechanisms of Nrf2 activation in esophageal squamous cell carcinogenesis in vivo. If successful, it will lay down a solid foundation for translational studies on Nrf2-high ESCC and contribute to reduction of cancer health disparity in the African American population.

Co-Principal Investigators

Luke Chen, PhD NCCU	Ben Major, PhD UNC Lineberger