# ITLN1, orchestrated by the IFNγ-IRF1 axis, suppresses hepatocellular carcinoma proliferation via ERK1/2 activation

## TL;DR

ITLN1, controlled by the IFNγ-IRF1 pathway, helps stop liver cancer growth by activating ERK1/2 signaling.

## Contribution

Identified ITLN1 as a tumor suppressor in HCC regulated by the IFNγ-IRF1 axis and ERK1/2 signaling.

## Key findings

- ITLN1 expression is reduced in HCC and correlates with poor survival.
- ITLN1 inhibits HCC proliferation and cell cycle progression via ERK1/2 activation.
- IFNγ-IRF1-ITLN1 axis suppresses HCC growth and is a potential therapeutic target.

## Abstract

•ITLN1 acts as a tumor suppressor in hepatocellular carcinoma (HCC).•Decreased expression of ITLN1 was indicative of poor overall survival in HCC.•ITLN1 attenuates HCC proliferation and induces cell cycle arrest.•ITLN1 protects against HCC via activation of ERK1/2 signaling.•IFNγ-IRF1-ITLN1 axis inhibits HCC cells proliferation and cell cycle progression.

ITLN1 acts as a tumor suppressor in hepatocellular carcinoma (HCC).

Decreased expression of ITLN1 was indicative of poor overall survival in HCC.

ITLN1 attenuates HCC proliferation and induces cell cycle arrest.

ITLN1 protects against HCC via activation of ERK1/2 signaling.

IFNγ-IRF1-ITLN1 axis inhibits HCC cells proliferation and cell cycle progression.

Intelectin 1 (ITLN1) is a recently discovered secretory adipokine with pivotal functions in the innate immune system, inflammation, and the facilitation of glucose uptake. Nonetheless, its exact functions in hepatocellular carcinoma (HCC) remain not fully elucidated.

In this study, ITLN1 was identified as a clinically significant secretory adipokine linked to HCC, validated through qRT-PCR, western blot, immunohistochemistry, and TCGA data. Its role in HCC was explored using CCK-8, clone formation, EdU, migration, and cell cycle assays, alongside xenograft tumor experiments. RNA sequencing, luciferase reporter assays, and ChIP assays confirmed ITLN1′s molecular mechanisms in inhibiting HCC proliferation.

Our study revealed that ITLN1 expression was significantly downregulated in HCC tissues compared to adjacent non-tumor tissues, and its reduced expression was associated with poor overall survival. Functionally, ITLN1 attenuated HCC proliferation in a cell cycle arrest manner via activation of ERK1/2 signaling. We also identified transcription factor interferon regulatory factor 1 (IRF1) as a regulator of ITLN1 through bioinformatics analysis and affirmed the binding site on the ITLN1 promoter. Furthermore, interferon-gamma (IFNγ), a classic upstream cytokine of IRF1, could promote ITLN1 expression through IRF1. Subsequently, the IFNγ-IRF1-ITLN1 axis was identified and found to inhibit HCC cell proliferation and cell cycle progression.

In summary, our study found that ITLN1, regulated by IFNγ-IRF1 axis, suppresses HCC proliferation by constitutively activating ERK1/2 signaling and holds promise as a prospective prognostic indicator and a plausible therapeutic target for HCC.