The latest finding by an international study borne by a collaboration between the Cleveland Clinic in the United States and the National Cancer Centre in Singapore revealed a loss of a single gene—GATA4—may drive the development of liver cancer.

“Losing the GATA4 gene is like losing one of the main guardians of the liver,” said Timothy Wai-ho Shuen, a Hongkonger who is a research fellow at the National Cancer Centre in Singapore, also one of the key authors of the study.

GATA4 responsible for liver cell proliferation and differentiation

What is GATA4? The researchers describe it as a “master transcription factor” that decides the ultimate fate of liver cells. A transcription factor is a protein that binds to cell DNA and regulates DNA expression—therefore being able to influence the workings of a cell.

Cancer arises from the overgrowth of abnormal cells that eventually results in a tumour. This is often caused by an error in DNA that results in uncontrolled division. With these concepts in mind, this team of scientists sought to determine if there is a transcription factor responsible for causing DNA alterations that eventually gives rise to liver cancer.

Missing GATA4 or mutations in GATA4 have also been implicated in heart malformations as well as lung, gastric and colorectal cancers.

Nearly half of the study cohort had a missing GATA4 gene

The team of researchers analysed tumour samples from patients who had liver cancer and compared them to healthy liver tissue. Among 55 patient cases, nearly half (44%) of them were found to miss out chromosome 8p, which encodes for GATA4.

The team took their research a step further by observing the effect of mice that were genetically altered to have only half of normal GATA4 activity. Interestingly, these mice developed livers that displayed much higher levels of precursor (‘young’) cells and failed to develop into mature liver cells. This is important as cancers often develop from immature cells that have a higher potential to regenerate, unlike mature cells that often lose this ability.

Additionally, the team discovered that the genetic profile of tissue samples of liver cancer had a reduced expression of about 2,486 genes compared to healthy liver samples. This finding underscores the possibility of yet-to-be-discovered genetic factors that may lead to liver cancer.

New findings open door to better treatments for liver cancer

The study authors are now seeking opportunities to collaborate with the University of Hong Kong (HKU) to investigate if Hongkongers with liver cancer displayed a missing GATA4 gene as well. If GATA4 is proved to be influential in the development of liver cancer, this would introduce new directions to develop therapies that combats GATA4 deficiencies and benefit liver cancer sufferers.

“A new understanding of pathways related to GATA4 deletion… now provides an unprecedented opportunity to seek out new targets for therapeutic intervention against liver cancer,” said Toh Han Chong, one of the study leaders and deputy director of the National Cancer Centre Singapore.

Currently, treatment for advanced liver cancer is not curative, and it can only prolong a patient’s life by an average of three months.

Liver cancer remains the second highest cause of cancer deaths globally. The East Asian population have the highest incidence of liver cancer in the world, followed by Africa and the Pacific Islands. According to data from the Centre for Health Protection (CHP), liver cancer accounts for 11% of all cancer deaths in Hong Kong. MIMS

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