# The Role of Long Noncoding RNAs in Cancer

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2023 · —

## Abstract

Hepatocellular cancer (HCC) is the 5th most common malignancy in the United States, and its incidence is
equally high in the Veteran population. Although liver cancer resection has proven to be an effective treatment
for localized disease, new therapeutic modalities are needed to treat unresectable disease. This is a 4-year
grant proposal to study epigenetic aspects of hepatocellular cancer in order to study the pathophysiology of
this deadly cancer and to begin to identify new therapeutic drug targets and/or define novel biomarkers for the
disease. Metabolic reprogramming is a major hallmark of cancer cells.
Due to the Warburg effect, tumor cells
preferentially bypass the tricarboxylic acid cycle and switch to glycolytic energy metabolism despite available
oxygen. Alterations in lipid and amino acid metabolism are also present. Currently, however, we know very little
about how this malignant metabolic switch is regulated in cancer. Mitochondria are master regulators that
modulate metabolic reprogramming. Mitochondria in malignant cells differ structurally and functionally from
those in normal cells and are characterized by overproduction of reactive oxygen species. Long noncoding
RNAs (lncRNAs)
are key regulators of metabolism that can modulate mitochondrial activity epigenetically. These
lncRNAs may be transcribed from either the mitochondrial or the nuclear genomes, and the lncRNAs may be
transported back and forth from the mitochondria to the cytoplasm to the nucleus. In Specific Aim 1, the
mitochondrial lncRNAs in human normal liver and
hepatocellular
cancer cell lines will be extensively profiled,
to learn which specific lncRNAs are involved in carcinogenesis. The molecular mechanisms whereby lncRNAs
shuttle back and forth between the mitochondria and the nucleus will be determined. In Specific Aim 2, the
roles of these lncRNAs will be assessed to gain a mechanistic understanding of how lncRNAs use epigenetic
processes to initiate or propagate
hepatocellular
cancer in order to devise strategies to prevent or treat the
disease. In addition to cultured cell lines, we will create tumoroids, organoids that are derived from
hepatocellular
cancer stem cells. These tumoroids recapitulate the development of malignant tumors in vitro,
providing a model system to learn which lncRNAs initiate, propagate and maintain the malignant state.
Innovative aspects of this grant include a new understanding of the role of lncRNAs in cancer, the development
of several novel molecular epigenetic tools that have broad applicability in developmental and cancer biology,
and the assembly of new databases of mitochondria-associated lncRNAs in cancer. The ultimate goal of the
project is to learn more about the pathophysiology and oncogenesis of
hepatocellular
cancer so that new drug
targets and/or biomarkers can be discovered to aid in the diagnosis and treatment of this deadly cancer in
male and female Veterans.

## Key facts

- **NIH application ID:** 10695989
- **Project number:** 5I01BX002905-08
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** ANDREW R HOFFMAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-01-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695989

## Citation

> US National Institutes of Health, RePORTER application 10695989, The Role of Long Noncoding RNAs in Cancer (5I01BX002905-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10695989. Licensed CC0.

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