# Novel noncanonical actions of CAR in human Liver

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $390,827

## Abstract

Project Summary
 The constitutive androstane receptor (CAR; NR1i3) is a well-established xenobiotic sensor that regulates the
expression of numerous genes encoding proteins important for drug metabolism and clearance. Accumulating
evidence suggests that CAR also plays noncanonical roles in coordinating diverse physiological and
pathophysiological responses associated with energy homeostasis and cell proliferation. Studies in rodents have
established activation of CAR as a key event promoting liver tumor formation. In contrast, CAR activation-
induced replicative DNA synthesis and hepatocyte proliferation in rodents were not observed in either cultured
human liver cells in vitro or in chimeric mice with humanized liver in vivo. Moreover, epidemiological studies have
shown that even after long-term clinical use, phenobarbital, a prototypical CAR activator, does not increase the
incidence of liver tumors in humans. Yet, the role of human CAR (hCAR) in hepatoma cell proliferation and liver
cancer development remains poorly understood. The overall objective of this application is to delineate the role
of hCAR in liver tumor progression and to develop a comprehensive understanding of the molecular mechanisms
underlying the effects of hCAR on hepatoma cell proliferation. To this end, we have shown that 1) expression of
hCAR was significantly lower in hepatocellular carcinoma (HCC) compared to normal liver and, importantly,
hCAR expression is inversely correlated with HCC outcomes; 2) ectopic expression of the reference hCAR but
not a splicing variant isoform (hCAR3) in hepatoma cells markedly repressed cell proliferation, soft agar colony
formation, and the growth of hepatoma xenografts in nude mice; 3) RNA-seq analyses revealed that hCAR alters
the expression of a cluster of tumor suppressors and oncogenes including the downregulation of erythropoietin
(EPO), a pleiotropic growth factor that exhibits cell proliferation and anti-apoptosis functions; and 4) activation of
human and mouse CAR differentially alters the expression of cell proliferation genes in vivo. Based on these
exciting preliminary findings, we hypothesize that in stark contrast to its rodent counterparts, hCAR exhibits
anticancer functions that repress the progression of HCC by downregulating EPO. This central hypothesis will
be tested in two Specific Aims: Aim 1. Define the role of hCAR isoforms in hepatoma cell proliferation and HCC
progression; and Aim 2. Delineate the mechanisms by which hCAR represses HCC progression. Our findings
are expected to determine the role of hCAR in HCC development and provide novel mechanistic insights into
hCAR-mediated suppression of HCC progression that will open the door to novel biomarkers and therapeutics.

## Key facts

- **NIH application ID:** 10445324
- **Project number:** 5R01CA262084-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Hongbing Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,827
- **Award type:** 5
- **Project period:** 2021-07-06 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445324

## Citation

> US National Institutes of Health, RePORTER application 10445324, Novel noncanonical actions of CAR in human Liver (5R01CA262084-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10445324. Licensed CC0.

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