ReviewRASSF1A: A promising target for the diagnosis and treatment of cancer
Introduction
Globally, cancer is a major cause of mortality. In 2030, approximately 22 million individuals will be diagnosed with cancer, and the number of cancer-related deaths will reach 13 million [1]. Cancer is a multi-factorial, multi-step, and prolonged biological process that involves complex interactions between genetic and environmental factors. Although most cancers are treated using multiple drugs that target different pathways to maximize the benefits of treatment, treatment effectiveness is often limited by tumor heterogeneity and drug resistance [2]. Therefore, there is an urgent need to design new drugs that target specific oncogenic molecules to implement personalized treatment and enhance therapeutic sensitivity and specificity.
The ras association domain family 1 isoform (RASSF1A), a tumor suppressor, located on chromosome 3p21 [3], responds to various stimuli by regulating cellular processes such as cell cycle arrest, migration, microtubular stabilization, and apoptosis promotion [4], [5]. An increasing body of evidence indicates that RASSF1A is epigenetically inactivated by promoter hypermethylation in a wide range of diseases [6], [7], [8]. Recently, studies have found that RASSF1A has a diagnostic role in cancer tissues [9], [10], [11] and enables early detection in liquid biopsies [12], [13], [14]. Hypermethylation of the RASSF1A promoter is frequently correlated to malignant pathologies including clinical stage, lymph node status, distant metastasis [15], [16], and drug resistance [17], which indicates that RASSF1A is involved in the initiation and progress of all major solid cancers. Up till now, research on anti-cancer therapy has focused on establishing new molecular interactions and control of drug resistance by reactivating RASSF1A in tumor cells [18], [19], [20].
Thus, hypermethylation of RASSF1A is a promising diagnostic and prognostic biomarker to better guide anti-neoplastic therapy, and demethylation of the RASSF1A promoter may also present a feasible anti-neoplastic strategy.
Section snippets
Lung cancer
Globally, lung cancer is the leading cause of cancer-related deaths [21]. Currently, low-dose Computed Tomography (CT) is routinely used to diagnose lung cancer in high-risk people. However, it has a high false-positive rate (96%) for the diagnosis of early lung cancer [22], [23]. Therefore, it is imperative to identify patients with lung cancer at earlier stages by a reliable marker. Cigarette smoking, an induced lung cancer factor, is associated with RASSF1A hypermethylation in Asians [24]. A
Clinical value of RASSF1A in liquid biopsies
Traditional diagnostic methods (serum markers, radiography, and endoscopy) have limited use for diagnosing cancers because of high costs, invasiveness, or imprecision in identifying highly heterogeneous tumors. Recent studies have shown that liquid biopsy has the potential to diagnose cancers [82], [83], [84], including circulating DNA, a reliable marker for monitoring the load, evolution, and heterogeneity of tumors in a non-invasive and reproducible manner.
Previous studies have demonstrated
Role of RASSF1A in different anti-tumor agents
An increasing number of studies have demonstrated that a hypermethylated RASSF1A level may predict or identify cancer patients who will not respond to anti-cancer treatment (Table3) [92], [93], [94]. The results of these studies can help discover novel therapeutic interventions and guide therapeutic decisions. Therefore, identification of hypermethylated RASSF1A is a key to determine cancer-acquired resistance and to develop a novel drug for cancer-related diseases.
Regulatory mechanism of RASSF1A in anti-resistance
Currently, drug resistance is one of the major obstacles in anti-cancer treatment, leading to disease relapse and patient mortality [135]. The mechanism of drug resistance is complicated; it includes drug efflux [136], DNA damage repair [137], epithelial-mesenchymal transition (EMT) [138], the emergence of cancer stem cells (CSCs) [139], and tumor microenvironment (TME) [140]. As mentioned previously, dysregulation of multiple targets and pathways by inactivation of RASSF1A resulted in drug
Conclusions
RASSF1A methylation has been studied in different clinical phases of cancer, from early stages to the identification of prognostic factors in early cancer, to the molecular characterization of metastatic disease and its relapse. However, we have to admit that evidence on the utilization of RASSF1A methylation is insufficient to guide treatment for daily clinical practice.
Mechanistically, a lower expression or inactivation of RASSF1A can dysregulate RAS, Hippo, Wnt, and other tumor-related
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by Hunan Provincial Innovation Foundation For Postgraduate, China (No. CX20190766), the Natural Science Foundation of Hunan Province (No. 2018JJ2356, 2019JJ80034).
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