Preface

Cancer is a malignant tumor caused by DNA damage, which leads to uncontrolled cell growth. Tumor progression is locally favored by the mitogenic effects of hormones or growth factors, which stimulate the tumor's growth, or the activation of vascular endothelial growth factor receptor, which induces angiogenesis and leads to metastasis. About 300 out of 25,000 genes that set up the human genome are involved in cancer pathology. These genes are divided into three groups: oncogenes, tumor suppressor genes, and DNA repair genes. Activated oncogenes promote the development of cancer, whereas the tumor suppressor and DNA repair genes have a protective role by respectively inhibiting cell cycle progression and inducing apoptosis, or by repairing DNA damage occurring during the cell cycle.

The purpose of this book is to discuss the topics of tumor suppressor genes and add to knowledge of the understanding of cancer using advanced biochemistry, cell, and molecular biology tools. Tumor suppressor genes can be used as targets of preventive therapy, markers of risk that can be used to identify populations at high risk, or markers of a drug's toxicity used in prevention, which can help to monitor its tolerance.

The book is divided in three sections and five chapters.

Section I: Studies of Potential Tumor Suppressor Genes (Chapter 1: N-Myc Downstream-Regulated Gene 2 (NDRG2) as a Novel Tumor Suppressor in Multiple Human Cancers; Chapter 2: METCAM/MUC18: A Novel Tumor Suppressor for Some Cancers).

Section II: Genes with Dual Suppressor and Oncogenic Activities (Chapter 3: Tumor Suppressor Genes with Oncogenic Roles in Lung Cancer; Chapter 4: Duplicitous Disposition of Micro-RNAs (miRs) in Breast Cancer).

Section III: Tumor Suppressor Proteins in Cell Signaling Pathways (Chapter 5: Regulation of HDACi-triggered Autophagy by the Tumor Suppressor Protein p53).

The first chapter discusses the role of the N-myc Downregulated Gene 2 (NDRG2) as a tumor suppressor gene in multiple cancers. *In vitro* and *in vivo* studies report cancer cell inhibition, metastasis cell differentiation, and cell cycle arrest mediated by NDRG2. The authors suggest that NDRG2 might be considered as a potential target for cancer therapeutics and treatment. However, the detailed mechanism requires further investigation to confirm its tumor suppressor function.

The role of METCAM/MUC18 as a possible tumor suppressor gene is reported in Chapter 2. METCAM/MUC18 is a cell adhesion molecule (CAM) that belongs to the Ig-like gene superfamily and is located in the human 11q23-3 chromosome. Multiple studies have shown evidence that METCAM/MUC18 might play a tumor suppressor role in many cancers, including mouse melanoma and human nasopharyngeal, ovarian, prostate, colorectal, hemangioma, and pancreatic cancers. Moreover, in some cancers such as nasopharyngeal cancers, METCAM/MUC18 plays a dual

suppressor and promoter role. Thereby, the authors suggest that METCAM/MUC18 could be used as a new therapeutics target for such cancer treatment.

In the third chapter the authors discuss the issue of tumor suppressor genes with dual suppressive and oncogenic roles in lung cancer. Among such genes, TP53 (a well-known tumor suppressor gene in many cancers) activating alterations can promote cancer development and progression, despite its classic functions of cell cycle regulation, DNA repair, senescence, and apoptosis, which give it the role of "guardian of the genome." The authors also describe the role of nuclear factor 1B (NF1B), which belongs to a transcription factor family, including NF1A, NF1B, NF1C, and NF1X. These transcription factors lead to DNA repression or activation of genes in a context-specific manner. NF1B in particular has been described as both an oncogene and a potential tumor suppressor gene. It is amplified and/or overexpressed in many types of cancers such as melanoma, breast and esophagus cancers, and in salivary glands. A lower expression of NF1B is associated with shorter average survival, less-differentiated tumor features, and repressed expression of cell differentiation markers in lung adenocarcinoma. A tumor suppressive role of NF1B has been suggested in non-small cell lung cancer. NOTCH is another gene acting as an oncogene in lung adenocarcinoma and has a potential role as a tumor suppressor gene. The authors also report the tumor suppressive functions of NKX2-1 in lung adenocarcinoma. This gene acts in the restriction of cell motility, invasion, and metastatic ability. The dual role of NKX2-1 depends on EGFR, KRAS, and TP53 status in lung adenocarcinoma. NKX2-1 acts by enhancing EGFR-driven tumorigenesis. Another gene with a dual role is the Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1). This gene has been previously identified as an oncogenic transcript and considered as a marker of metastasis, poor patient survival, and chemotherapy resistance in non-small cell lung cancer. MALAT1 promotes carcinogenesis through p53 deacetylation and enhances cell migration. In contrast, MALAT1 has been shown to reduce invasiveness in PTEN-expressing tumors. For example, MALAT1 reduces invasiveness of cerebral metastasis by sustaining the blood–brain barrier.

In the fourth chapter, the author provides an overview of the role of microRNAs (miRNAs) in breast cancer. The miRNAs are highly conserved in humans but are not translated into proteins. However, these molecules are involved in gene regulation and carcinogenesis. The miRNAs have dual roles in cancer pathology. Several miRNAs are both cancer and tissue specific. Because the primary role of miRNAs is to decrease target mRNA expression, they are upregulated by cancer cells aren, often those that support cancer growth and are called oncomirs. Other miRNAs are downregulated and referred to as tumor suppressor miRNAs. Since miRNAs are released by cancer cells in the blood, the author concludes by suggesting that both monitoring and targeting miRNAs enables the diagnosis and monitoring of breast cancer as well as the opportunity for the development of novel therapeutics.

Studies in the fifth and final chapters report regulation by the tumor suppressor protein p53, the most common tumor suppressor gene, of autophagy mediated by histone deacetylase inhibitors (HDACi) in cancer cells. The authors refer to the cellular mechanism of autophagy and describe biological signaling pathways regulated by tumor suppressor protein p53 in the formation of autophagosomes, the HDACiinduced cell death.

I am grateful to the IntechOpen Access Publisher team for giving me the opportunity to be the editor of this book. I am particularly thankful to Ms. Ivana Barac, the Publishing Process Manager, for guiding me through the publication process

**V**

and coordinating the different steps. I would like to thank all the authors who have contributed to this book by writing their chapters and for making my requested revisions to them. I also thank them for sharing their knowledge of the understanding of carcinogenesis surrounding the issue of tumor suppressor genes. I dedicate this book to all my colleagues and students at Université des Sciences de la Santé of Libreville, Gabon. Lastly, I would like to thank my family for their support throughout my academic career, particularly Jeanne-Otoua, Marie-Thérèse Moungala, and my wife Sophie-Mindili for their understanding during this book project process.

**Guy Joseph Lemamy, PhD**

Molecular Biology-Genetics

Libreville, Gabon

Professor and Head of Department of Cellular and

Faculty of Medicine, University of Health Sciences

(Faculté de Médecine, Université des Sciences de la Santé),

and coordinating the different steps. I would like to thank all the authors who have contributed to this book by writing their chapters and for making my requested revisions to them. I also thank them for sharing their knowledge of the understanding of carcinogenesis surrounding the issue of tumor suppressor genes. I dedicate this book to all my colleagues and students at Université des Sciences de la Santé of Libreville, Gabon. Lastly, I would like to thank my family for their support throughout my academic career, particularly Jeanne-Otoua, Marie-Thérèse Moungala, and my wife Sophie-Mindili for their understanding during this book project process.

#### **Guy Joseph Lemamy, PhD**

Professor and Head of Department of Cellular and Molecular Biology-Genetics

Faculty of Medicine, University of Health Sciences (Faculté de Médecine, Université des Sciences de la Santé), Libreville, Gabon

**IV**

induced cell death.

suppressor and promoter role. Thereby, the authors suggest that METCAM/MUC18

In the third chapter the authors discuss the issue of tumor suppressor genes with dual suppressive and oncogenic roles in lung cancer. Among such genes, TP53 (a well-known tumor suppressor gene in many cancers) activating alterations can promote cancer development and progression, despite its classic functions of cell cycle regulation, DNA repair, senescence, and apoptosis, which give it the role of "guardian of the genome." The authors also describe the role of nuclear factor 1B (NF1B), which belongs to a transcription factor family, including NF1A, NF1B, NF1C, and NF1X. These transcription factors lead to DNA repression or activation of genes in a context-specific manner. NF1B in particular has been described as both an oncogene and a potential tumor suppressor gene. It is amplified and/or overexpressed in many types of cancers such as melanoma, breast and esophagus cancers, and in salivary glands. A lower expression of NF1B is associated with shorter average survival, less-differentiated tumor features, and repressed expression of cell differentiation markers in lung adenocarcinoma. A tumor suppressive role of NF1B has been suggested in non-small cell lung cancer. NOTCH is another gene acting as an oncogene in lung adenocarcinoma and has a potential role as a tumor suppressor gene. The authors also report the tumor suppressive functions of NKX2-1 in lung adenocarcinoma. This gene acts in the restriction of cell motility, invasion, and metastatic ability. The dual role of NKX2-1 depends on EGFR, KRAS, and TP53 status in lung adenocarcinoma. NKX2-1 acts by enhancing EGFR-driven tumorigenesis. Another gene with a dual role is the Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1). This gene has been previously identified as an oncogenic transcript and considered as a marker of metastasis, poor patient survival, and chemotherapy resistance in non-small cell lung cancer. MALAT1 promotes carcinogenesis through p53 deacetylation and enhances cell migration. In contrast, MALAT1 has been shown to reduce invasiveness in PTEN-expressing tumors. For example, MALAT1 reduces invasiveness of cerebral metastasis by sustaining the blood–brain barrier.

In the fourth chapter, the author provides an overview of the role of microRNAs (miRNAs) in breast cancer. The miRNAs are highly conserved in humans but are not translated into proteins. However, these molecules are involved in gene regulation and carcinogenesis. The miRNAs have dual roles in cancer pathology. Several miRNAs are both cancer and tissue specific. Because the primary role of miRNAs is to decrease target mRNA expression, they are upregulated by cancer cells aren, often those that support cancer growth and are called oncomirs. Other miRNAs are downregulated and referred to as tumor suppressor miRNAs. Since miRNAs are released by cancer cells in the blood, the author concludes by suggesting that both monitoring and targeting miRNAs enables the diagnosis and monitoring of breast cancer as well as the opportunity for the development of novel therapeutics.

Studies in the fifth and final chapters report regulation by the tumor suppressor protein p53, the most common tumor suppressor gene, of autophagy mediated by histone deacetylase inhibitors (HDACi) in cancer cells. The authors refer to the cellular mechanism of autophagy and describe biological signaling pathways regulated by tumor suppressor protein p53 in the formation of autophagosomes, the HDACi-

I am grateful to the IntechOpen Access Publisher team for giving me the opportunity to be the editor of this book. I am particularly thankful to Ms. Ivana Barac, the Publishing Process Manager, for guiding me through the publication process

could be used as a new therapeutics target for such cancer treatment.

**1**

Section 1

Studies of Potential Tumor

Suppressor Genes

## Section 1
