Elsevier

Clinica Chimica Acta

Volume 504, May 2020, Pages 98-108
Clinica Chimica Acta

Review
RASSF1A: A promising target for the diagnosis and treatment of cancer

https://doi.org/10.1016/j.cca.2020.01.014Get rights and content

Highlight

  • RASSF1A is a promising biomarker in the screening, staging and therapeutic management in human malignancies.

  • Hypermethylated RASSF1A may identify cancer-acquired resistance and develop a novel drug for cancer-related diseases.

  • RASSF1A inactivation can dysregulate the RAS, Hippo, Wnt and other tumor-related signaling pathways, which potentially results in drug resistance.

Abstract

The Ras association domain family 1 isoform A (RASSF1A), a tumor suppressor, regulates several tumor-related signaling pathways and interferes with diverse cellular processes. RASSF1A is frequently demonstrated to be inactivated by hypermethylation in numerous types of solid cancers. It is also associated with lymph node metastasis, vascular invasion, and chemo-resistance. Therefore, reactivation of RASSF1A may be a viable strategy to block tumor progress and reverse drug resistance. In this review, we have summarized the clinical value of RASSF1A for screening, staging, and therapeutic management of human malignancies. We also highlighted the potential mechanism of RASSF1A in chemo-resistance, which may help identify novel drugs in the future.

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).

References (186)

  • E. Van Cutsem et al.

    Gastric cancer

    Lancet

    (2016)
  • K. Tzartzeva et al.

    Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis

    Gastroenterology

    (2018)
  • J.C. Lin et al.

    DNA methylation markers and serum alpha-fetoprotein level are prognostic factors in hepatocellular carcinoma

    Ann. Hepatol.

    (2015)
  • J. Langstein et al.

    Impact of DNA methylation programming on normal and pre-leukemic hematopoiesis

    Semin. Cancer Biol.

    (2018)
  • A. Avramouli et al.

    Methylation status of RASSF1A in patients with chronic myeloid leukemia

    Leuk. Res.

    (2009)
  • H. Wang et al.

    Real-time monitoring efficiency and toxicity of chemotherapy in patients with advanced lung cancer

    Clin. Epigenet.

    (2015)
  • K. Ito et al.

    Utility of liquid biopsy by improved PNA-LNA PCR clamp method for detecting EGFR mutation at initial diagnosis of non-small-cell lung cancer: observational study of 190 consecutive cases in clinical practice

    Clin. Lung Cancer

    (2018)
  • A.A. Ponomaryova et al.

    Potentialities of aberrantly methylated circulating DNA for diagnostics and post-treatment follow-up of lung cancer patients

    Lung Cancer (Amsterdam, Netherlands)

    (2013)
  • A. Ogden et al.

    Docetaxel-induced polyploidization may underlie chemoresistance and disease relapse

    Cancer Lett.

    (2015)
  • J. Ferlay et al.

    Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012

    Int. J. Cancer

    (2015)
  • F. Dubois et al.

    Levallet G.RASSF1A, puppeteer of cellular homeostasis, fights tumorigenesis, and metastasis-an updated review

    Cell Death Dis.

    (2019)
  • A. Liao et al.

    Hu H.RASSF1A inhibits gastric cancer cell proliferation by miR-711- mediated downregulation of CDK4 expression

    Oncotarget

    (2016)
  • S. Kristiansen et al.

    Detection and monitoring of hypermethylated RASSF1A in serum from patients with metastatic breast cancer

    Clin. Epigenet.

    (2016)
  • R.H. Salama et al.

    Interrelations of apoptotic and cellular senescence genes methylation in inflammatory bowel disease subtypes and colorectal carcinoma in egyptians patients

    Appl. Biochem. Biotechnol.

    (2019)
  • V. Leiro et al.

    Methylation assessment for the prediction of malignancy in mediastinal adenopathies obtained by endobronchial ultrasound-guided transbronchial needle aspiration in patients with lung cancer

    Cancers (Basel)

    (2019)
  • Z. Kozomara et al.

    Promoter hypermethylation of p16, BRCA1 and RASSF1A genes in triple-negative breast cancer patients from Serbia

    J. Buon

    (2018)
  • S.P. Nunes et al.

    Subtyping lung cancer using DNA methylation in liquid biopsies

    J. Clin. Med.

    (2019)
  • H.F. Pasha et al.

    RASSF1A and SOCS1 genes methylation status as a noninvasive marker for hepatocellular carcinoma

    Cancer Biomark

    (2019)
  • Z. Zhang et al.

    Correlation between RASSF1A gene promoter hypermethylation in serum or sputum and Non-Small Cell Lung Cancer (NSCLC): a meta-analysis

    Med. Sci. Monitor: Int. Med. J. Exp. Clin. Res.

    (2019)
  • A.M. Grawenda et al.

    Clinical utility of RASSF1A methylation in human malignancies

    Br. J. Cancer

    (2015)
  • M. Khandelwal et al.

    Decitabine augments cytotoxicity of cisplatin and doxorubicin to bladder cancer cells by activating hippo pathway through RASSF1A

    Mol. Cell. Biochem.

    (2018)
  • D. Pankova et al.

    O'Neill E.RASSF1A controls tissue stiffness and cancer stem-like cells in lung adenocarcinoma

    The EMBO J.

    (2019)
  • S. Dabral et al.

    A RASSF1A-HIF1alpha loop drives Warburg effect in cancer and pulmonary hypertension

    Nat. Commun.

    (2019)
  • S.J. Oh et al.

    Ras association domain family 1 isoform A suppresses colonic tumor cell growth through p21(WAF1) activation in a p53-dependent manner

    J. Gastroenterol. Hepatol.

    (2019)
  • D. Leong et al.

    Advances in adjuvant systemic therapy for non-small-cell lung cancer

    World J. Clin. Oncol.

    (2014)
  • D.R. Aberle et al.

    Reduced lung-cancer mortality with low-dose computed tomographic screening

    New Engl. J. Med.

    (2011)
  • P. Pinsky et al.

    Long-term cancer risk associated with lung nodules observed on low-dose screening CT scans

    Lung cancer (Amsterdam, Netherlands)

    (2019)
  • X.M. Wu et al.

    Association between cigarette smoking and RASSF1A gene promoter hypermethylation in lung cancer patients: a meta- analysis

    Asian Pac. J. Cancer Prevent. : APJCP

    (2014)
  • H. Hu et al.

    Prognostic value of RASSF1A methylation status in non-small cell lung cancer (NSCLC) patients: A meta-analysis of prospective studies

    Biomarkers: Biochem. Indicators Exposure Response Suscept. Chem.

    (2019)
  • S.S. Nazari et al.

    An overview of mammographic density and its association with breast cancer

    Breast cancer (Tokyo, Japan)

    (2018)
  • E. Warner

    Clinical practice. Breast-cancer screening

    New Engl. J. Med.

    (2011)
  • K. Kerlikowske et al.

    Outcomes of screening mammography by frequency, breast density, and postmenopausal hormone therapy

    JAMA Intern. Med.

    (2013)
  • E. Jezkova et al.

    Impact of RASSF1A gene methylation on the metastatic axillary nodal status in breast cancer patients

    Oncol. Lett.

    (2017)
  • C. Wright et al.

    Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer

    Cancer Res.

    (1989)
  • D.F. Hayes

    HER2 and Breast Cancer - A Phenomenal Success Story

    New Engl. J. Med.

    (2019)
  • A.C. Wolff et al.

    Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update

    Arch. Pathol. Lab. Med.

    (2014)
  • T. Swift-Scanlan et al.

    Methylated genes in breast cancer: associations with clinical and histopathological features in a familial breast cancer cohort

    Cancer Biol. Ther.

    (2011)
  • M. Li et al.

    Diagnostic value of RASSF1A methylation for breast cancer: a meta-analysis

    Biosci. Rep.

    (2019)
  • X. Xing et al.

    The prognostic value of CDKN2A hypermethylation in colorectal cancer: a meta-analysis

    Br. J. Cancer

    (2013)
  • S. Sanduleanu et al.

    Laterally spreading tumor through the magnifying glass: we only see what we know

    Endoscopy

    (2016)
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