The Impact of Developmental Regulation on Aging and Cancer

Author

Yun Zhu, Southern Illinois University CarbondaleFollow

Date of Award

12-1-2021

Degree Name

Doctor of Philosophy

Department

Molecular Biology, Microbiology and Biochemistry

First Advisor

Yuan, Rong

Second Advisor

Nie, Daotai

Abstract

Aging is a major risk factor for a variety of diseases, including metabolic disease and cancer. Accumulating evidence suggests that the regulation of developmental traits might have long-term effects on aging and health conditions later in life. The current project focuses on understanding the underlying genetic and molecular mechanisms. Nuclear receptor interacting protein 1 (NRIP1, also named RIP140) is a key regulator that modulates transcriptional activity of variety of transcription factors, including estrogen receptor and NF-κB. We previously identified that NRIP1 plays an important role in development and aging. The global depletion of Nrip1 (Nrip1-/-) significantly reduced pre-weaning survival, delayed female sexual maturation, improved insulin sensitivity at young, middle, and old age, as well as increased the longevity of female mice. In the current project, using adipose tissue- derived stem cells (ASCs), we found that the benefits of suppressing NRIP1 on aging and longevity may be related to reduced inflammation, delayed cell senescence and cell growth, and improved stem cell maintenance. The elucidation of the role of NRIP1 in female reproduction, metabolism, inflammation, and cell senescence, encouraged us to further investigate the role of NRIP1 in breast cancer. Importantly, epidemiological studies of human populations found that an early age at menarche significantly associates with risk of breast cancer (BC). During development, depletion of NRIP1 delays female sexual maturation and suppresses the development of mammary glands. Our previous study showed that NRIP1 expression was elevated in breast cancer, and that the depletion of NRIP1 could suppress the onset and progression of breast cancer. Combining this study with the findings of suppressed inflammation and delayed cell senescence, we hypothesized that Nrip1 knockout may have anti-BC effect by improving the stroma cell function and lowering the inflammation in local microenvironment. In this study, we found that NRIP1 is not only involved in tumorigenesis of breast cancer, but also in the cancer progression and the development of drug resistance. Interestingly, suppressing Nrip1 in a tamoxifen-resistant breast cell line restored drug sensitivity. The mechanism of anti-cancer effect may be related to suppressed NF-κB expression and activity, as well as reduced expression of aromatase.While identifying genes that are involved in development and longevity is important to aging research, searching for geroprotective drugs for clinical use may be a more realistic way to improve metabolic traits and delay aging in humans. Metformin is a widely used drug for treating type 2 diabetes (T2D) that has a good safety profile. Also, metformin treatment has been linked to a reduced risk of cancer and cancer-related mortality in retrospective investigations. In this study, heterogeneous mice (UM-HET3) were treated with metformin between the ages of 15 and 56 days. The results show that body weight and food consumption were increased, and sexual maturation was delayed in females. Tail length and circulating insulin-like growth factor 1 (IGF1) levels were significantly increased. Glucose tolerance was improved, but no significant difference in insulin tolerance was found. Circulating adiponectin and insulin levels were altered by metformin treatment. Analysis of quantitative insulin sensitivity check index (QUICKI) suggests that metformin treatment increased insulin sensitivity. These results revealed that treating mice early in life with metformin alters development and metabolism. Importantly, the effects of metformin treatment at an early age may have long-term impacts on health and aging-related traits.