# Arsenic-induced miRNA-199 and miRNA-214 deplete mitochondrial DNA for the generation of cancer stem-like cells

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2020 · $263,563

## Abstract

We have shown that consecutive treatment of the human bronchial epithelial cells with the
environmentally relevant concentration of As3+ (0.125 – 0.25M), an environmental metalloid metal, for
six months, induces transformation of the human bronchial epithelial cells, some of which possess
characteristics of the cancer stem-like cells (CSCs), such as tumor sphere formation in vitro, self-
renewal in vivo, increased expression of the stemness genes, including Oct4, Sox2, KLF4, and c-myc.
In addition, these cancer stem-like cells exhibited a pronounced increase in the expression of several
microRNAs, most notably, the miR-214, miR-199, miR-10b, miR-34b, etc. Furthermore, integrated
transcriptomic and metabolomic analyses demonstrated a higher rate of glycolysis and lower levels of
mitochondrial metabolism due to mitochondrial DNA (mtDNA) depletion among these As3+-induced
CSCs. Lastly, a unique glycolytic feature that is different from naïve embryonic stem cells (ESCs) and
cancer cells was found in these As3+-induced CSCs. Both ESCs and cancer cells direct glycolysis for
lactate production. In contrast, the As3+-induced CSCs show increased conversion of the glycolytic
intermediates into the subsidiary pathways for the generation of N-acetylglucosamine important for O-
GlcNAcylation of the stemness genes and the S-adenosyl methionine (SAM) that contributes to DNA
and histone methylation. Accordingly, the goal of this application is to determine: (1) is As3+-induced
miRNAs, esp. miR214/199, responsible for the depletion of mtDNA and the consequent inhibition of
mitochondria; (2) if so, how miRNAs induced by As3+ impairs the integrity and function of mtDNA and
mitochondria; and (3) how the impaired function of mitochondria contributes to the generation of the
CSCs induced by As3+. We hypothesize that As3+-induced JNK-dependent pSTAT3S727 and miR-214/199
switch mitochondrial OXPHOS to glycolysis for the formation of CSCs. To test this hypothesis, the following
three specific aims are proposed: Specific Aim 1: As3+-activated JNK and pSTAT3S727 enforce
expression of miR-214 and miR-199 that down-regulate mitochondrial transcription factor A (TFAM) in
BEAS-2B and other lung cells for the generation of CSCs. We will focus on the transcriptional regulation
of the miR-214/199 cluster with emphases on promoter DNA methylation and transcription factor
binding in cellular response to As3+ and its down-stream signaling; Specific aim 2: Understand how
As3+-induced JNK, miR-214/199 and mitochondrial dysfunction contribute to the formation of CSCs with
an emphasis on metabolic reprogramming from OXPHOS to glycolysis. Specific Aim 3: Defining the
causal roles of As3+-induced JNK- and miR-214/199-dependent metabolic reprogramming in the
changes of epigenetics related to chromatin structure and accessibility that linked to self-renewal and/or
differentiation of the As3+-induced CSCs through high-throughput profiling. We will identify metabolite-
dependent epigenetic a...

## Key facts

- **NIH application ID:** 9926262
- **Project number:** 5R01ES028335-03
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Fei Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $263,563
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926262

## Citation

> US National Institutes of Health, RePORTER application 9926262, Arsenic-induced miRNA-199 and miRNA-214 deplete mitochondrial DNA for the generation of cancer stem-like cells (5R01ES028335-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9926262. Licensed CC0.

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