# Decoding Oral Carcinogenesis and Tumor Progression in Whole Cigarette Smoke Exposure: A Systematic Review

## TL;DR

This review explores how whole cigarette smoke contributes to oral cancer development and progression at the molecular level in human oral cells.

## Contribution

The study systematically compiles molecular mechanisms of oral carcinogenesis caused by whole cigarette smoke exposure.

## Key findings

- Cigarette smoke exposure affects heme metabolism, miRNA-145, and NOD1/BiP expression in oral cells.
- Modulation of MMP-2, MMP-9, and cathepsin, along with RAGE signaling, is linked to tumor progression.
- The review highlights the broader impact of whole cigarette smoke on oral cancer beyond individual carcinogens.

## Abstract

This systematic review aims to highlight the molecular mechanisms by which whole cigarette smoke affects oral carcinogenesis and its progression in human oral cells, based on evidence from original research articles published in the literature. A literature search was conducted using three databases: Web of Science, Scopus, and PubMed from May to June 2024. The articles were screened, and the data were extracted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (2020). The included studies were subsequently evaluated using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool for bias factors. From the 14 included studies, two types of cell lines were frequently utilized: human oral mucosal epithelial cells or oral squamous cell carcinoma cells. In these cell lines, one of three forms of exposure was applied: cigarette smoke, its extract, or condensate. The mechanism of oral carcinogenesis and tumor progression includes aberrations in the heme metabolic pathway, modulation of miRNA-145, NOD1 and BiP expression, MMP-2, MMP-9, and cathepsin modulation, abnormal TSPO binding, RIP2-mediated NF-κB activation, MZF1-mediated VEGF binding, and activation of the RAGE signaling pathway. In conclusion, cigarette smoke significantly influences the development and progression of oral squamous cell carcinoma, based on the evidence highlighted in human oral cells. While previous studies have focused on specific carcinogens and pathways, this review added to our understanding of the overall impact of whole cigarette smoke on oral carcinogenesis at the molecular and cellular levels.