Zinc and Esophageal Cancer

Author: Federico Garrou
Date: 10/07/2014



The esophagus is a muscular tube that runs between the throat and the stomach. It lies behind the trachea (windpipe) and in front of the spine.
The wall of the esophagus has several layers. These layers are important for understanding where cancers in the esophagus tend to start and how they can grow.

Mucosa: This layer lines the inside of the esophagus.

The mucosa has 3 parts:

• The epithelium forms the innermost lining of the esophagus and is normally made up of flat, thin cells called squamous cells. This is where most cancers of the esophagus start.
• The lamina propria is a thin layer of connective tissue right under the epithelium.
• The muscularis mucosa is a very thin layer of muscle under the lamina propria.

Submucosa: This is a layer of connective tissue just below the mucosa that contains blood vessels and nerves. In some parts of the esophagus, this layer also includes glands that secrete mucus.

Muscularis propria: This is a thick layer of muscle under the submucosa. It contracts in a coordinated, rhythmic way to push food along the esophagus from the throat to the stomach.

Adventitia: This is the outermost layer of the esophagus, which is formed by connective tissue.

Esophageal cancer

Cancer of the esophagus starts in the mucosa and grows outward through the submucosa and the muscle layer. Since 2 types of cells can line the esophagus, there are 2 main types of esophageal cancer:

1. Squamous cell carcinoma
This kind of cancer starts in the squamous cells which normally line the esophagus.

2. Adenocarcinoma
Cancers that start in gland cells are called adenocarcinomas. This type of cell is not normally part of the inner lining of the esophagus.
Before an adenocarcinoma can develop, gland cells must replace an area of squamous cells.
This occurs mainly in the lower esophagus, which is where most adenocarcinomas start.

Symptoms often include trouble swallowing and weight loss. Other symptoms may include pain with swallowing, a hoarse voice, enlarged lymph nodes (glands) around the clavicle (collarbone), a dry cough, and possibly coughing up or vomiting blood.

The disease is diagnosed by biopsy done by an endoscope (a fiberoptic camera).

Regarding the incidence, The American Cancer Society’s estimates for esophageal cancer in the United States for 2014 are:
• About 18,170 new esophageal cancer cases diagnosed (14,660 in men and 3,510 in women)
• About 15,450 deaths from esophageal cancer (12,450 in men and 3,000 in women)
This disease is 3 to 4 times more common among men than among women. The lifetime risk of esophageal cancer in the United States is about 1 in 125 in men and about 1 in 435 in women

( What is cancer of the esophagus?. 2014 )

The critical role of miR-21 and miR-31

Epidemiological and clinical studies have implicated dietary zinc deficiency (ZD) in the pathogenesis of esophageal squamous cell carcinoma (ESCC) because it dysregulates two important factors control: miR-31 and miR-21.
In 2012 Research Professor H. Alder published an important work on Oxford Journals with which it has been shown that in zinc deficiency esophagus there is an overexpression of oncogenic miR-31 and miR-21 accompanied by down-regulation of their respective tumor-suppressor targets:

miR-21 --> PDCD4 and TPM1

miR-31 --> PPP2R2A and RHOBTB1 and STAU2

Esophageal miR-31 and miR-21 high levels were directly associated with the appearance of ESCC.
Situ hybridization analysis in human localized miR-31 to tumor cells and miR-21 to stromal cells.
The role of these two oncomiRs in esophageal neoplasia was further explored:

miR-21 is one of the most consistently up-regulated oncomiRs in human cancers.
Data show that miR-21 overexpression in inflammatory ZD esophagus is correlated with down-regulation of its tumor-suppressor targets PDCD4 and TPM1.
In human ESCC, miR-21 negatively regulates PDCD4 and knockdown of miR-21 inhibits cellular proliferation and invasion.
Loss of PDCD4 protein expression is correlated with cancer aggressiveness (tumor stage, nodal metastasis)

miR-31 is a pleiotropically acting miRNA that is up-regulated in many types of human cancers, including ESCC.
miR-31 overexpression in ZD esophagus is accompanied by down-regulation of its known tumor-suppressor target PPP2R2A.
The role of PPP2R2A has not been reported in human ESCC but researchers speculate that the down-regulation of such tumor-suppressor targets may relate to the increased cell proliferation and inflammation associated with zinc deficiency.

miR-31 may serve as a noninvasive diagnostic marker for a premalignant esophageal condition. In fact, patients with ESCC display high levels of miR-31 as well as miR-21 in tumor tissues and in serum/plasma.

Mechanical events are not fully understood yet but, from a molecular point of view, it is considered that the connection between the levels of zinc and miR-21 and miR-31 is represented by transcription factors known as "zinc fingers."

( Dysregulation of miR-31 and miR-21 induced by zinc deficiency promotes esophageal cancer. 2012 )

Zinc Fingers

Zinc fingers are small protein structural motif characterized by the coordination of one or more zinc ions in order to stabilize the fold. The name has now come to encompass a wide variety of differing protein structures.

Zinc finger proteins are among the most abundant proteins in eukaryotic genomes. Their functions are extraordinarily diverse and include DNA recognition, RNA packaging, transcriptional activation, regulation of apoptosis, protein folding and assembly, and lipid binding. Zinc finger structures are as diverse as their functions. Structures have recently been reported for many new zinc finger domains with novel topologies, providing important insights into structure/function relationships. In addition, new structural studies of proteins containing the classical Cys(2)His(2) zinc finger motif have led to novel insights into mechanisms of DNA binding and to a better understanding of their broader functions in transcriptional regulation

( Zinc finger proteins: new insights into structural and functional diversity. 2001 )


Includes mainly stopping smoking and a healthy diet
Global dietary zinc deficiency is estimated to affect 30% of the population, with
higher frequencies occurring in developing countries.
Individuals subsisting largely on a cereal diet or on a strict vegetarian diet are
likely to be zinc deficiency.

Daily intake recommendations for zinc and other nutrients are provided in the
Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB)
at the National Academy of Sciences (Washington DC).

Sources of Zinc

A wide variety of foods contain zinc.
Oysters contain more zinc per serving than any other food, but red meat and poultry provide the majority of zinc in the American and European diet.
Other good food sources include beans, nuts, certain types of seafood (such as crab and lobster), whole grains, fortified breakfast cereals, and dairy products.

Phytates, which are present in whole-grain breads, cereals, legumes, and
other foods, bind zinc and inhibit its absorption.
Thus, the bioavailability of zinc from grains and plant foods is lower
than that from animal foods, although many grain- and plant-based foods
are still good sources of zinc

molecule of phytate

( Zinc: Fact Sheet for Health Professionals. 2013 )


Zn-sufficient diets are an important factor in the prevention of esophageal cancer.
However, ingestion of amounts greater than 150 mg / day of zinc has undesirable metabolic effects, such as immune dysfunction and impaired antioxidant defense, which are potentially related to esophageal cancer.

( Zinc Toxicity. 2014 )

2014-09-28T22:17:31 - Federico Garrou
2014-09-28T22:13:51 - Federico Garrou
2014-09-28T22:11:44 - Federico Garrou
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