Malignant mesothelioma (MM) affects the mesothelium cell lining. These include the lining around the heart, the tunica vaginalis testis, the lungs, and the abdomen. There are three types of mesothelioma, namely the epithelioid, sarcomatoid, and biphasic. Malignant mesothelioma is mainly caused by exposure to asbestos fibers. It is considered a rare and deadly disease ^[1][2][1,2] with median overall survival of 9–18 months [3]. The incidence of MM has had a worldwide gradual increase over the past years and is predicted to be at its highest in 2020 [4]. However, the disease is highly misdiagnosed in Sub-Saharan African (SSA) countries. A significant number of SSA communities still use asbestos products and most of these are housing structures. Concerns around exposure to asbestos fibers are mainly associated with the mining industry [5]. This notion might be skewed as some of the small community members who do not work nor reside near the mines have succumbed to mesothelioma or some kind of undiagnosed lung disease.

The CpG methylation profiles were identified as independent predictors of patient survival. Epigenetic alterations observed in cancers vs. non-cancerous samples correlated with asbestos body burden, providing evidence that asbestos exposure characterizes tumors into specific epigenetic subclasses. Irregular epigenetic mechanisms are shown to be responsible for the induction of malignant pleural mesothelioma (MPM) [6]. DNA methylation is a well-studied epigenetic modification in cancer ^[7][8][7,8]. This modification is responsible for guiding cell characterization through gene expression, genome stability, or blocking the interaction between DNA and related transcription factors ^[9][10][9,10]. Cancer cells take advantage of dysregulated DNA methylation by targeting CpG islands in gene expression regulatory machinery [10].

MicroRNA (miRNA) are non-coding RNAs in which their expression is in part regulated by other epigenetic features, such as DNA methylation and histone modifications [11]. It has long been established that miRNA expression is dysregulated in mesothelioma [12] and these miRNAs target cell-cycle transcription factors whilst being regulated by the components of the cell cycle themselves. These features reflect an indication of their importance as potential therapeutic biomarkers of diseases such as MM [13]. The other well-studied key regulator of the immune system is the microbiome. The microbiome assists in the development and maturation of the immune system. The balance between the host immune system and microbiome contributes immensely to susceptibility to inflammatory diseases (bearing in mind that cancer is considered a chronic inflammatory disease) later in life. The gut microbiome has been shown to have an impact on cancer immunosurveillance ^[14][15][14,15], and this impact is mainly attributed to microbiota in mesotheliomas [16]. Thus, it is important to understand how epigenetic modifications and interactions with microbiome and related immune responses could provide potential therapeutic targets for the early diagnosis and treatment of MM.

2. The Burden of Asbestos-Related Diseases, a Persisting Challenge

The global incidence of mesothelioma increased during the period of 1990 to 2017. Over 50% of the cases recorded were from high socio-demographic index (SDI) regions. The age-standardized incidence rate (ASIR) decreased from 1.11 to 0.17% in Southern SSA after 2000 but increased from 2.03 to 2.30% in Australasia. In this study, Zhai et al. reported that the global trends of mesothelioma vary amongst countries, but according to the authors, the incidence of mesothelioma has decreased since 1990 [17]. Screening and early detection of mesotheliomas remains a challenge; hence, the incidence of the disease is not well recorded. The lack of resources in the LMICs could be a limiting factor in terms of diagnosing and recording mesothelioma incidences and mortality rates as expected. Recently, Chimed-Ochir et al. evaluated the correlation of country-level mesothelioma burden and asbestos use with national income status. The study looked at 80 high-income countries of which 54 (68%) reported mesothelioma deaths to WHO. The low-middle-income countries (LMICs) were 78, and only 11 (14%) of these countries reported mesothelioma deaths. The other 86% of these deaths were not reported. The highest number of mesothelioma deaths were recorded by high-income and upper-middle-income countries at 29,854 (78%), whilst LMICs reported only 8534 (22%) deaths [18]. This study echoes the need for social and scientific community awareness campaigns so that the communities are aware of the dangers of occupational and household asbestos products. The companies that still produce products that contain asbestos need to be evaluated by health professionals and inspected regularly. The need to facilitate the implementation of the regulations to control asbestos exposure should be considered. Finally, simpler reliable screening methods that can be utilized even in rural areas for early detection of asbestos-related diseases should be ventured into. In LMICs such as India, the continual use of asbestos products is remarkable. Jadhav and Gawde, 2019 predict that the country will experience a high incidence of asbestos-related diseases accounting for at least 1.25 million patients diagnosed with cancer worldwide [19]. The latency of mesothelioma is long and highly variable with a range of 13–70 years meaning that although the disease is considered rare, there is a chance that the numbers are yet to increase among people who have been exposed to asbestos before the ban or implementation of regulatory measures. The socioeconomic status in rural SSA regions makes the decision to eliminate the use of asbestos difficult as transitioning from asbestos roofing to metal sheets, for example, can be costly. Owing to its long, covert pathogenesis and latency, scientists in the SSA regions do not pay much attention to the disease as it is not necessarily obvious like other cancers commonly diagnosed in the region. There is thus the need to find better ways of diagnosing the disease with consideration of the asbestos exposure situation in LMICs like SSA and India in mind. There is a possibility that more and more cases of mesothelioma will emerge. There will have to be measures implemented to ensure that these cases are not missed and efforts to improve the quality of life are undertaken. Wagner et al. reported cases of mesothelioma induced by exposure to asbestos originating from the mines. However, one of the cases was peculiar as the patient had never worked at the mines. The relatives of the patient also mentioned no previous knowledge of asbestos exposure neither through the mining industry nor factories manufacturing asbestos production [20]. Although it is a major problem, repurposing of asbestos products for household purposes in these communities is still a normal practice. For example, asbestos sheets can be used to dry animal skin or meat prepared for traditional ceremonies. The manufacturing of asbestos products used to be a lucrative business for South Africa. The discovery of its detrimental effects on human health led to the ban of the production of asbestos products in the country. It is important to note that there is still a substantial number of houses with asbestos cement roof sheets. Guidelines for the demolition of these structures have been set by the National Institute for Occupational Health (NIOH) of South Africa. The NIOH also analyzed the samples removed from the structures and measures the asbestos fibers post demolition. Although not all of the structures were demolished, 2990 samples were collected from 3/9 provinces in the country (Gauteng, Mpumalanga, and the Western Cape). A total of 1581 bulk samples were collected. The study found that 54.8% of the bulk samples contained asbestos, and 16.1% (227) of asbestos was found in air filters post demolition [21]. This is a potential indication of how asbestos fibers escape into the air during demolition; hence, the area of demolition must be well contained. Efforts to prevent asbestos-related diseases require implementation of a set of sequential measures. Ideally, this would include managing and removing the existing asbestos housing structures and asbestos-related products replacing them with alternative materials such as iron sheet roofing; exposure to occupational asbestos fibers can be limited by taking preventative measures such as training employees on asbestos exposure and related risks; in cases where exposure is unavoidable, training on how to safely handle asbestos and related products should be implemented; the use of personal protective equipment (PPE) where necessary should be encouraged; regular measurements of asbestos fibers in the air should be done. Perkins et al. reiterated the significance of enough wetting during the demolition processes as it assists with the reduction of airborne materials including asbestos fibers [22].

3. The Role of miRNA in Mesothelioma

The miRNAs involved in oncogenesis pathways are reduced in MM encouraging the development of miRNAs mimics for possible reversal of cancer initiation processes [23]. Studies done on experimental models have demonstrated the possibility of reversing oncogenesis by reintroducing specific miRNAs identified as tumorigenic. For instance, treatment of MPM tumor xenografts with ectopically re-expressed miR-206 showed a significant reduction of tumor growth achieved via G1/S cell cycle arrest. The effectiveness of miR-206 was shown to be controlled by the RTK-Ras-MAPK-PI3K/Akt-CDK pathway. This effect allowed the authors to ascertain the use of CDK6 as a novel target for miR-206 [24]. Similarly, treatment with miRNA-215-5p diminished cancer growth by activation of mouse double minute 2 (MDM2)-p53 signaling pathway and resultant caspase-dependent apoptosis [25]. The miR-126 located within intron 7 of its host gene EGFL7 is downregulated in MPM. The EGFL7 S2 region methylation status was associated with significantly worse MPM patient survival. These results correlated well with the downregulation of EGFL7 transcript variant 1 and miR-126 [26]. Significant downregulation of miR-126 is strongly correlated with serum levels of vascular endothelial growth factor (VEGF) [27] and soluble mesothelin-related peptide (SMRP). SMRP was previously identified as a possible diagnostic marker for MPM [28]. Follow-up studies identified pleural effusion SMRP as a better indicator of MPM over serum SMRP [29]. The MDM2 along with other factors such as TRAIL [30]/HIF-1α [31] involved in MPM have been investigated as therapeutic targets or potential biomarkers, respectively. Identification of miRNA as potential therapeutic targets of MM has been a topic of interest for a while, these include miR-16 [32], miR-193a-3p [33], miR-17-5p in relation to KCa1.1 [34], and miR-411, which controls the expression of IL-18 [35] (Table 1). Targeting miRNAs and related pathways continue to be the topic of interest today.