4. The guardian of the genome: p53

epithelium [15]. Therefore, the differentiated esophageal squamous epithelial cells might be able to transform back to columnar cells. Does it sound possible? However, in vitro study demonstrated that acid and/or bile treatment upregulated CDX-2 expression in normal esophageal epithelial cells (Het1A), which led to intestinal phenotype [16]. The esophageal epithelium is maintained by a distinct group of p63-expressing stem cells beneath the mucosa under the influence of a specific cue within the organ. When the esophagus is insulted by acidic refluxate repeatedly, the progenitor cells lose p63 expression and are misled to differentiate into columnar instead of squamous epithelial cells. This is where the second theory stands [17]. Does it sound reasonable? More evidence is needed. The third theory seems pretty strong, because it is supported by experimental evidence. In 2008, Sarosi et al. successfully transplanted female rats that had been surgically induced by reflux esophagitis with bone marrow from male rats and later identified Y-chromosome in half of the esophageal epithelial cell population, indicating a colonization of bone marrow stem cells in esophageal epithelium [18]. However, Aikou et al. conducted similar experiment using mice and could not confirm bone marrow-derived metaplastic esophageal epithelial cells [19]. Nevertheless, both the second and third theories recognize the important contribution from stem cells during metaplastic transformation. The only difference is the origin of progenitor cells. If bone marrow stem cells could be misguided to differentiate into columnar phenotype where squamous cells are supposed to be, why could not the local stem cells? The fourth theory has also found experimental evidence in human. In 2014, Lavery et al. showed that labeled gastric cells residing in the middle of esophageal glands had undergone metaplastic transformation, suggesting that esophageal columnar epithelial cells could be

Table 1. The top five of the most commonly mutated genes () and the top five of the most highly expressed genes (+) in ESCC.

transformation, apoptosis

EGFR EGF receptor Mediating EGF signaling + [13]

Gene Protein Function Up (+)/down ()

response, cell death

CCND1 Cyclin D1 Cell cycle progression + [9] TP63 p63 Transcription regulator + [9] SOX2 Sex determining region Y 2 Embryogenesis, stem cell maintenance + [9]

CDKN2A p16 Stabilizing p53 — [11, 12] KDM6A Lysine demethylase 6A Chromatin remodeling — [9] KMT2D Lysine methyltransferase 2D Chromatin remodeling — [9]

TP53 p53 Tumor suppression, cellular stress

MYC c-myc Cell cycle progression, cell

RB1 Retinoblastoma transcriptional corepressor 1

4 Esophageal Cancer and Beyond

in ESCC

Tumor suppression — [10]

— [11]

+ [9]

References

The next question is how esophageal metaplasia turns into EAC. There are two main theories currently. The first theory thinks that EAC develops from Barret's esophagus through a stepwise

from the migration of gastric cardiac columnar epithelial cells [20].

Based on multiple genetic analyses performed by several independent groups [9, 27–29], TP53 always appeared to be the most frequently mutated gene in both ESCC and EAC. Not just esophageal malignancy, 50–60% of human cancers that have been studied so far contain homozygous mutations in TP53 [30]. That is almost to say, p53 has to be disabled in order to turn a normal cell into a cancerous cell. Why is p53 so important?

TP53 encodes a transcription factor named p53, which has only 393 amino acids. It functions as a tetramer of two dimers, each binding a sequence RRRCWWGYYY (R = A/G, W = A/T, Y = C/ T). When a gene contains two such sequences separated by 0–13 base pairs, it becomes a potential target of p53. Up to date, out of 30,000 human genes known so far, 3661 have been found to contain such p53 response elements. In another word, more than 10% of our entire genome is possibly under p53 regulation. Among these target candidates, 346 have been confirmed to be bound and regulated by p53, including 246 upregulated by p53, 91 downregulated by p53, and nine can go either way [31]. That is to say, p53 has the power to shut a gene down or open it up, "all up to its mood."

miR-25) have been found to directly bind to p53 mRNA and block it from translation and thereby allow cancer cell to proliferate. By the same principle, microRNAs targeting the suppressors of p53 can indirectly fight for p53 protein stability and activity. For instance, miR-192 increases p53 accumulation by targeting MDM2 mRNA; miR-191 supports p53

Introductory Chapter: Esophagus and Esophageal Cancer

http://dx.doi.org/10.5772/intechopen.77995

7

[1] Chai J, Jamal MM. Esophageal malignancy: A growing concern. World Journal of Gastro-

[2] Malhotra GK, Yanala U, Ravipati A, Follet M, Vijayakumar M, Are C. Global trends in

[4] Chen W, Sun K, Zheng R, Zeng H, Zhang S, Xia C, Yang Z, Li H, Zou X, He J. Cancer incidence and mortality in China, 2014. Chinese Journal of Cancer Research. 2018;30:1-12

[5] Castellsagué X, Muñoz N, De Stefani E, Victora CG, Castelletto R, Rolón PA, Quintana MJ. Independent and joint effects of tobacco smoking and alcohol drinking on the risk of esophageal cancer in men and women. International Journal of Cancer. 1999 Aug 27;

[6] Eriksen MP, Mackay J, Schluger NW, et al. The Tobacco Atlas. Georgia: American Cancer

[7] Brown LM, Hoover R, Silverman D, Baris D, Hayes R, Swanson GM, Schoenberg J, Greenberg R, Liff J, Schwartz A, Dosemeci M, Pottern L, Fraumeni JF Jr. Excess incidence of squamous cell esophageal cancer among US black men: Role of social class and other

[8] Corley DA. Obesity and the rising incidence of esophageal and gastric adenocarcinoma:

risk factors. American Journal of Epidemiology. 2001 Jan 15;153(2):114-122

esophageal cancer. Journal of Surgical Oncology. 2017 Apr;115(5):564-579

[3] Chai J. Esophageal Abnormalities. Croatia: Intech Publisher; 2017

stability by blocking MDM4 translation, and miR-34a initiates attacks on YY1 mRNA.

\*Address all correspondence to: jianyuan.chai@gmail.com

2 School of Medicine, University of California, Irvine, USA

enterology. 2012 Dec 7;18(45):6521-6526

1 Baotou Medical College, Baotou, China

Author details

Jianyuan Chai1,2\*

References

82(5):657-664

Society Publishing, Atlanta; 2015

What is the link? Gut. 2007;56:1493-1494

Normally, after translation, p53 is degraded rapidly through ubiquitination by MDM2, an E3 ubiquitin ligase that happens to be a true target gene of p53. In another word, p53 is a well selfdisciplined molecule and can take good care of itself and would not allow itself to accumulate unnecessarily. In response to cellular stresses like DNA damage, oncogene activation, or hypoxia, however, p53 dissociates from MDM2 through various protein modifications such as phosphorylation, acetylation, or methylation, becoming an active transcription factor. Then, p53 rolls out a transcriptional program, namely activating certain genes and/or suppressing some others, to cause cell cycle arrest, senescence, or apoptosis, thereby managing the cellular crisis and bringing the microenvironment back to normal. For this reason, p53 has earned the honor as the "guardian of the genome," and also for this reason, a cell must depower p53 first in order to become malignant.

There are several ways to depower p53 in a cell. Gene mutation is the first one. As mentioned earlier, more than 50% of cancers have TP53 mutations. Interestingly, a majority of these mutations (~ 90%) are missense. In another word, the mutated gene can still be transcribed into a protein product, just different from the wild-type p53. Furthermore, most of these mutations take place at ~190 codons, which encoding the amino acid residues 102–292 within the DNA-binding domain of the transcription factor. Some of the mutant p53 protein products still possess DNA-binding capability to a degree, just weaker, about 0–75% of the wild-type p53 depending on the exact location of the mutation. This is also believed to be the reason for different cancerous phenotypes. Environmental carcinogens tend to cause selective mutations within TP53 and thereby lead to tissue-specific cancers. For instance, tobacco smoke (carcinogen: benzoapyrene diol epoxide) tends to induce mutations at G245 V, G245C, and R249M, which are commonly seen in association with ESCC patients [32]. In vitro studies have demonstrated that the expression of mutant p53 in normal cells with TP53 deletion gives them new properties like rapid proliferation, loss of contact inhibition, accelerated migration/invasion, and tumorigenic potential in nude mice, which are the properties that a cancer cell usually possesses, further indicating TP53 mutations in favor of cancer development.

Compared to gene mutation, posttranscriptional regulations also play a significant role in depowering p53. As discussed earlier, p53 protein is constantly degraded by MDM2-mediated ubiquitination. MDM4, a homolog of MDM2, can suppress p53 activation as well, and so do several others, like SIRT1, YY1, MTA2, and HDAC1. Cancer cells learn to cast curses on p53 by overexpressing these proteins in case TP53 mutation did not work. The expression of microRNAs is another example. Several species of microRNAs (i.e., miR-125b, miR-504, and miR-25) have been found to directly bind to p53 mRNA and block it from translation and thereby allow cancer cell to proliferate. By the same principle, microRNAs targeting the suppressors of p53 can indirectly fight for p53 protein stability and activity. For instance, miR-192 increases p53 accumulation by targeting MDM2 mRNA; miR-191 supports p53 stability by blocking MDM4 translation, and miR-34a initiates attacks on YY1 mRNA.
