Lung cancer (LC) is the second most common cancer in both genders, and it is the leading cause of cancer mortality globally (Siegel et al. 2022). Approximately 2.2 million new LC cases were diagnosed worldwide with nearly 1.8 million deaths in 2020 ([CSL STYLE ERROR: reference with no printed form.]). Lung cancer is caused by the uncontrolled cell growth in the tissues of the lung and is classified into two major histological types: small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC) (Travis et al. 2015). NSCLC accounts for 80%-85% of lung cancers. Although the main etiologic factor is tobacco use, other risk factors such as occupational exposures to hazardous chemicals, air pollution, poor diet and genetic susceptibility may also increase the risk of LC (Malhotra et al. 2016). Since smoking cessation policies were implemented, a downward trend has been reported in the incidence of LC in the developed countries. However, developing nations, such as China -where tobacco consumption has remined high- have not experienced a decline in LC incidence (Thandra et al. 2021). With the introduction of low-dose CT screening, important developments in the timely diagnosis of LC have been made in recent years (Nielsen and Fredberg 2022). However, to date, most lung cancers are diagnosed at an advanced stage, at stages 3 or 4, when the efficacy of treatment is more limited (Horst et al. 2020; Peterson 2023). LC continues to constitute a major health burden throughout the world, particularly in developing countries, therefore identifying new, effective options for the treatment of LC is crucial.
The TP53 gene is a widely researched tumor suppressor gene, located on chromosome 17. As one of the most frequently mutated genes in human cancers (Kandoth et al. 2013), coding the tumor protein p53, it regulates the expression of a range of genes from DNA repair, metabolism, cell cycle arrest to cell senescence and apoptosis (Vogelstein et al. 2000). TP53 has been found to be associated with the development of various cancers, including lung cancer (Mogi and Kuwano 2011).
The long intergenic non-protein coding RNA TP53-induced transcript (LINC-PINT) is a TP53-induced transcript, located on chromosome 7, spanning 232,616 bases (2021). Long non-coding RNAs (lncRNA) are a kind of RNA with more than 200 nucleotides which are not translated into protein (Балашенко and Дромашко 2017). With the development of genome-wide sequencing and high-resolution microarray technologies (Muers 2011; Gao et al. 2019), lncRNAs have been shown to be linked to gene transcription, post-transcriptional regulation, epigenetic regulation, and DNA regulation (Ponting et al. 2009).
LINC-PINT is considered to be a promising lncRNA tumor suppressor gene. Decreased expression levels of LINC-PINT have been found in various cancers such as osteosarcoma (Liu 2019), gastric cancer (Feng et al. 2019), renal cell carcinoma (Duan et al. 2019), glioblastoma (Zhang et al. 2018), melanoma (Xu et al. 2019), and lung cancer (Wang et al. 2020), including NSCLC (Zhang et al. 2019). Hence, LINC-PINT has been investigated as a possible marker for promoting tumor progression (He et al. 2021) and predicting prognosis (Jain 2020).
LincRNA-P21 is also a direct transcriptional target of TP53 (Jain 2020) and has been reported to play a part downstream of TP53-mediated transcriptional repression. By interacting with heterogeneous nuclear ribonucleoprotein K (hnRNP K), and TP53 upregulated modulator of apoptosis (PUMA), lincRNA-P21 regulates growth arrest and apoptosis (Huarte et al. 2010; Yang et al. 2019). In addition, lincRNA-P21 also interacts with MDM2 to regulate TP53 levels (Huarte et al. 2010). LincRNA-P21 has been found to directly or indirectly influence the proliferation, migration, apoptosis and the Warburg effect of cancer cells, by binding to different miRNAs and proteins (Huang et al. 2022). Thus, the possible role of lincRNA-P21 as a new biomarker in cancer has been suggested.
Molecular hydrogen (H2) is a colorless, odorless, and flammable gas. It has been utilized as a novel medical gas since its possible therapeutic effects were first investigated in vivo, in mouse skin squamous carcinoma (Dole et al. 1975). H2 has been reported to be a selective antioxidant, by decreasing the free radicals, ·OH and ONOO- in living cells (Ohsawa et al. 2007). H2 has also been found to interact with superoxide dismutase (SOD), adenosine triphosphate (ATP), nuclear factor erythroid 2-related factor 2 (Nrf2) and cytoplasmic heme oxygenase-1(HO-1) (Yu et al. 2014; Dong et al. 2018; Zhou et al. 2019). Hence, the anti-inflammation and anti-apoptotic properties of H2 have led to its increased investigation in anticancer research (Itoh et al. 2009; Hong et al. 2014).
The aim of the present study was to explore the therapeutic effect of H2 in lung cancer cells by determining the expression levels of LINC-PINT and lincRNA-P21.