Main TSGs with dual functions reported in lung cancer.
Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide. High-throughput sequencing efforts have uncovered the molecular heterogeneity of this disease, unveiling several genetic and epigenetic disruptions driving its development. Unlike oncogenes, tumour suppressor genes negatively regulate cell cycle control and exhibit loss-of-function alterations in cancer. Although tumour suppressor genes are more frequently disrupted, oncogenes are more likely to be drug-targeted. Many genes are described as presenting both tumour suppressive and oncogenic functions in different tumour types or even within the natural history of the disease in a single tumour. In this chapter, we describe current knowledge of tumour suppressor genes in lung tissues, focusing on tumour suppressor/oncogene duality.
- tumour-suppressor genes
- dual roles
- lung cancer
- targeted therapy
Cancer cells arise in non-malignant tissue due to the sequential acquisition of molecular alterations that drive proliferation, permit the evasion of growth suppression and apoptosis signals and promote angiogenesis, invasion and metastasis . This process is stochastic, and over time the tumour continues to evolve in a dynamic manner, generating a group of cells harbouring different genetic and epigenetic features . The resulting heterogeneity is the basis of tumour evolution and leads to the selection of tumour cells. These cells often present with rewired signalling networks and often oncogene addiction .
The uncontrolled growth of cancer cells can in part be explained by their aberrant gene expression patterns. While most cancer genes are characterized as either oncogenes or tumour suppressors based on their typical behaviour in tumours, some genes display dual oncogenic and tumour suppressive functions [4, 5]. The majority of these genes encode multiple isoforms, which are further post-translationally modified and form a variety of protein complexes, generating a context-dependent cellular network . In diploid organisms, gain-of-function (GOF) mutations in oncogenes are typically dominant (single events are sufficient to promote tumourigenesis), while loss-of-function alterations are recessive in TSGs (requires two inactivation events) . For example, for a TSG with dual oncogenic roles, one gain-of-function mutation can potentially cease its tumour suppressive function and turn on oncogenic signalling .
Recently, genes with both oncogenic and tumour-suppressive functions were described across 12 main cancer types using The Cancer Genome Atlas (TCGA) database . Using a text mining approach, the authors identified genes mainly represented by kinases (e.g.
In this chapter, we discuss TSGs with both tumour suppressive and oncogenic functions in lung cancer.
1.1 Lung cancer classification
Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide . In the United States, lung cancer accounts for 13.5% of all new cancer cases and 25.3% of all cancer deaths. The five-year survival rate is dismal, with only 18.6% of patients surviving 5 years . The majority of lung cancer cases (approximately 80%) are attributed to cigarette smoking . About 10–25% of cases occur in people who have never smoked . The aetiology behind these cases is most likely a combination of genetic factors, as well as the effects of exposure to environmental carcinogens such as asbestos, radon gas or other forms of pollution .
Lung cancer is classified according to histological type. There are two major types: small cell lung cancer (SCLC), which accounts for 15–20% of lung cancer patients, and non-small cell lung cancer (NSCLC), comprising the remaining 80–85% (Figure 1) . SCLC, primarily originating from the central airways, is thought to be derived from neuroendocrine cells . NSCLC is composed of three major histological subtypes: adenocarcinoma (LUAD), squamous cell carcinoma (LUSC) and large cell carcinoma (LCC). LUAD is the most common, accounting for approximately 40% of all lung cases . LUAD typically arises from glandular epithelium, from bronchioalveolar stem cells, club (Clara) cells or type II pneumocytes in the lung periphery . LUAD is also the predominant subtype that arises in patients who have never smoked . LUSC develops primarily in the central airways and segmental bronchi, strongly associates with a history of smoking and accounts for approximately 20% of all lung cancer cases. LCC may arise anywhere in the lung and are classified as tumours without general features associated with SCLC, LUAD or LUSC .
1.2 TSG mutation spectrum in lung cancer
Beyond the histological heterogeneity of lung cancer, genomic studies of large cohorts have uncovered the complex molecular landscape of lung tumours. Indeed, it has been observed that a wide variety of oncogenes and TSGs can be altered in lung cancer, and these molecular events are vastly different between histological subtypes [16, 17].
Clinical studies have shown that molecularly defined lung cancer subgroups can correlate with characteristics such as ethnicity , smoking history , treatment sensitivity  or prognosis . Many of the commonly identified gain-of-function alterations in proto-oncogenes have been actively investigated for therapeutic purposes. For example,
Three TSGs are frequently mutated in all three major lung cancer subtypes:
2. TSGs with oncogenic roles in lung cancer
Several TSGs in lung cancer have also been shown to behave as oncogenes, depending on the molecular context and/or the mechanism by which they are altered (Table 1). Among them are
|Gene||Main function||Role as TSG||Role as oncogene|
|TF: regulates cell cycle, DNA repair, senescence and apoptosis||TSG in several tissues: frequently lost through mutations ||Missense mutations confer gain-of-function oncogenic properties |
|TF: crucial in lung development||Underexpressed in NSCLC and associated with poor survival in LUAD ||Amplified and OE in SCLC: inducing chromatin reprogramming during metastasis |
|Transmembrane receptors: proliferation, differentiation and survival||Inactivated by inhibitor ligands and through mutations, especially in SCLC ||Maintains stem cell features; promotes proliferation in LUAD |
|TF: cellular defense mechanism against oxidative stress||Protects lung tissue against exposure to oxidative stress ||Mutational activation: aids cells to escape from endogenous tumour suppression |
|TF: essential for lung development||Acts as a TSG in
||Enhanced oncogenic signals in
|Serine-threonine kinase: regulation of energetic metabolism and cell polarity||Mutational inactivation promotes cancer development ||OE maintains metabolic homeostasis and attenuates oxidative stress |
|Cytokine: regulates development, differentiation and homeostasis||Expression loss leads to growth arrest in early-stage lung and other cancers ||OE promotes tumour growth in advanced cancer stages |
|Endoplasmic reticulum protein in magnesium uptake, glycosylation and embryonic development||Hypermethylation; expression loss in NSCLC; inhibits cell proliferation and promotes apoptosis ||OE in NSCLC accelerates cancer growth; induces EMT |
|TF: role in urogenital system development||Loss of function enhances cell viability and proliferation in Wilms’ tumour ||OE promotes survival in
|Long non-coding RNA||OE reduces invasiveness in PTEN expressing tumours ||OE associated with chemotherapy resistance in NSCLC |
|microRNA||OE induces apoptosis ||OE promotes metastasis |
|miR-378||microRNA||OE reverses chemoresistance to cisplatin in LUAD ||OE is associated with invasion and brain metastasis |
Despite having a reputation as a ‘guardian of the genome’, recent work has shown that activating
Lung cancer is commonly associated with tobacco use, where the prolonged exposure to carcinogens damages the DNA of the exposed cells. These alterations are especially enriched in missense mutations in
In lung cancer mouse models, prevention of tumour formation by inhibiting GOF p53 mutants has been demonstrated . Although the highly aberrant genomes in p53-mutated tumours should lead to unfeasible mitosis, these mutations facilitate the survival and proliferation of these cells through stabilizing replication forks and promoting micronuclei arrangement .
GOF p53 mutants are most likely involved in multiple mechanisms that coordinate tumour progression. For example, GOF-p53 (R175H, R273H and D281G) was demonstrated to upregulate
Nuclear factor I (NFI) is a transcription factor family, comprising NFIA, NFIB, NFIC and NFIX, that plays important roles in normal development and in numerous diseases . These proteins bind to specific DNA sequences leading to repression or activation of gene expression in a context-dependent manner, regulating cell differentiation and proliferation through their target genes .
A gene fusion involving
NOTCH gene family
The Notch signalling pathway is important in the regulation of cell fate during embryogenesis and maintenance of homeostasis in adult tissues . It includes Notch receptors (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) and ligands from the DSL family, which suppress or induce tumour-related mechanisms under specific cellular contexts .
In SCLC, Notch signalling is frequently inactivated by either a mutation in Notch receptors or the overexpression of ligands that inhibit downstream signalling . Despite this potential role as a TSG, Notch signalling in lung tumours is complex, as it has also been shown to be related to chemoresistance in SCLC . In addition, the overactivation of this pathway through several mechanisms acts like an oncogene in LUAD by preserving stem cell features and promoting proliferation [35, 73]. Notch1 expression is required in Kras-driven LUAD carcinogenesis, suppressing apoptosis via the p53 pathway . The inhibition of the Notch pathway is able to restrain lung cancer stem cell maintenance, which is characterized by subpopulations of cells expressing aldehyde dehydrogenase .
Conversely, loss-of-function mutations of Notch receptors generating truncated receptors imply a TSG role in LUSC . Although functional studies to further corroborate this hypothesis are still needed, reports in other squamous cell carcinomas substantiate the idea that the inactivation of this signalling pathway promotes tumourigenesis .
NKX2-1 (also known as TTF-1)
Nkx2-1 is a homeobox-containing transcription factor that is essential for lung development and is expressed in type II pneumocytes and bronchiolar cells in adults . It is expressed in 40–50% of lung cancers and is amplified and overexpressed in 6–11% of LUAD .
Nkx2-1 acts as a lineage-specific oncogene in some LUAD cases , enhancing cell viability and proliferation in lung cancer cell lines . This function relies on the activation of (i) the pro-survival PI3K-AKT pathway, through ROR1 kinase-dependent c-Src activation as well as maintaining the EGFR-ERBB3 association , and (ii) LMO3, a member of the LMO family of oncogenes that is translocated in T-ALL .
On the other hand,
Due to the constant exposure to oxidative stress in the lung, the
MALAT1 and other non-coding RNAs
While large-scale genomic sequencing efforts have uncovered an invaluable number of genetic alterations related to cancer biology, in the past, they were commonly focused on the 2% of the genome that encodes protein . In the last decade, non-coding RNA transcripts have been shown to have important regulatory functions in normal and disease biology . Indeed, many non-coding genes have been shown to play tumour-suppressive or oncogenic roles in numerous cancer types .
Metastasis-associated lung adenocarcinoma transcript 1 (
MicroRNAs (miRNAs) are short transcripts that typically regulate coding genes post-transcriptionally through direct interaction with mRNA transcripts. Many are deregulated in lung cancer , where they have documented tumour-suppressive and oncogenic roles . For example, miRNA-125b has been shown to have a multifaceted function as a tumour suppressor and oncogene, being underexpressed in bladder  and ovarian cancer  and overexpressed in glioma  and prostate cancer . It was shown that miRNA-125b induces apoptosis in cancer cell lines exposed to nutrient starvation and chemotherapy, including in lung cancer . On the other hand, miRNA-125b may also function as an oncogene in NSCLC, as it is able to promote metastasis by targeting TP53INP1 . In addition, inhibition of miR-125b can also decrease the invasive potential and leads to cell cycle arrest and apoptosis in NSCLC . Similarly, miR-378 was reported to be overexpressed in lung cancer and other tumour types, inducing cell migration, invasion and tumour angiogenesis . However, it was previously demonstrated that upregulation of this miRNA sensitizes lung cancer cell lines to cisplatin .
3. Conclusions and future directions
Here, we summarize the commonly disrupted genes in lung cancer with dual roles as both tumour suppressors and oncogenes. These conflicting roles are a result from the complexity of biological pathways and the heterogeneity of cancer cells.
Most of the current molecular therapies are based on hyperactivated oncogene inhibitors. In lung cancer, only a fraction of the cases exhibit alterations in targetable genes, such as
Considering that TSGs are found altered more frequently than oncogenes in human tumours , the existence of TSGs with dual oncogenic roles opens a new window of opportunities for the development of new targeted therapies. However, therapeutic action against TSGs remains challenging, as many are not amenable to current pharmacologic inactivation strategies. Most of the TSGs are not a kinase that can be pharmacologically blocked and are not located at the cell surface to be targeted by an antibody.
In summary, there is an unmet need to clarify the ambiguity found within genes, both coding and non-coding, with both pro- and anti-tumour functions. Broadening our understanding of these features may enable the development of novel and specific therapeutic strategies that consider both molecular and tissue contexts.
This work was supported by grants from the Canadian Institutes for Health Research (CIHR FDN-143345) and scholarships from CIHR, the BC Cancer Foundation, the Ligue nationale contre le cancer, the Fonds de Recherche en Santé Respiratoire (appel d’offres 2018 emis en commun avec la Fondation du Souffle), the Fondation Charles Nicolle and the São Paulo Research Foundation (FAPESP 2015/17707-5 and 2018/06138-8). D.D.B.S. and E.A.M. are Vanier Canada Scholars.
Conflict of interest
The authors have no conflicts to declare.
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