# Project 3: lncRNA SNHG1 and ATG7 in Basal-subtype Muscle-invasive Bladder Tumorigenesis

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $328,468

## Abstract

PROJECT 3: SUMMARY 
The major goal of this project is to study the molecular mechanisms that underlie the critical steps of bladder 
cancer (BC) progression: invasion and metastasis. Specifically, we will focus on how autophagy-related gene 7 
(ATG7)-mediated autophagy signaling drives BC cell invasion in vitro and metastasis in vivo. During the last 
funding period, we found that basal-subtype muscle-invasive bladder cancer (MIBC) in mice induced by bladder 
carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) markedly overexpress ATG7 and long non-coding 
RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1), and have significantly upregulated autophagy. In 
stark contrast, knockin mice lacking the RING domain of XIAP, which are completely resistant to BBN-induced 
basal MIBCs, have markedly reduced autophagy. We also found that, during BBN-mediated bladder 
tumorigenesis, the RING domain of XIAP is essential for SNHG1 overexpression, and that ectopic expression of 
SNHG1 in vitro induces autophagy and promotes BC cell invasion accompanied by upregulated ATG7, MMP2 
and MMP9. Furthermore, we showed that knockdown of ATG7 strongly inhibits autophagy, abolishes BC cell 
invasion and reduces the expression of basal MIBC marker KRT14. These data reveal a heretofore unknown 
role of autophagy in basal MIBC formation. Based on these data, we hypothesize that the upregulation of SNHG1 
and ATG7 by the RING domain of XIAP, and the autophagic signaling that these molecules trigger play critical 
roles in the genesis and progression of basal MIBC. We will test this hypothesis in three Specific Aims. Aim 1 
will define the regulatory circuitry in the SNHG1/ATG7/autophagy signaling axis that is operative in basal MIBC 
in vitro. Aim 2 will determine the biological effects of the SNHG1/ATG7/autophagy signaling on BC cell invasion 
in vitro and tumorigenesis and metastasis in vivo. Aim 3 will test the hypotheses that overexpression of SNHG1 
in basal urothelial cells of transgenic mice promotes basal MIBC formation, and that ablation of ATG7 in these 
cells of knockout mice renders mice resistant to basal MIBC formation and progression. These complementary 
approaches will provide definitive evidence regarding the in vivo roles of SNHG1 and ATG7 in the formation and 
progression of basal MIBC. While invasion and metastasis are the main reasons of the high mortality caused by 
MIBC, very little is known about the principal molecules or pathways that drive these crucially important biological 
processes. Our proposed studies that are highly focused on an important, but poorly understood signaling 
pathway comprising SNHG1/ATG7/autophagy should yield critical information on not only the underlying 
mechanisms, but also novel prognostic biomarkers to differentiate MIBC subtypes and new druggable targets to 
treat this aggressive form of BC.

## Key facts

- **NIH application ID:** 10455731
- **Project number:** 5P01CA165980-09
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** DIANE M SIMEONE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $328,468
- **Award type:** 5
- **Project period:** 2013-09-12 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455731

## Citation

> US National Institutes of Health, RePORTER application 10455731, Project 3: lncRNA SNHG1 and ATG7 in Basal-subtype Muscle-invasive Bladder Tumorigenesis (5P01CA165980-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10455731. Licensed CC0.

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