April 18, 2024

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How mutant KRAS and p53 can together promote pancreatic cancer?

How mutant KRAS and p53 can together promote pancreatic cancer?


How mutant KRAS and p53 can together promote pancreatic cancer?  It is the first time to reveal how mutant KRAS and p53 can promote the development and metastasis of pancreatic cancer, providing a new target for pancreatic cancer treatment. 

Pancreatic Cancer is a highly malignant malignant tumor of the digestive tract that is difficult to diagnose and treat. Pancreatic cancer has many subtypes, 90% of which are pancreatic ductal adenocarcinoma (PDAC).

In recent years, the incidence and mortality of pancreatic cancer have increased significantly. The early diagnosis rate of pancreatic cancer is not high, and it is often at an advanced stage when discovered. At this time, cancer cells have spread and are difficult to treat. The 5-year survival rate is less than 7%, which is the most prognostic Poor malignant tumors, so it is also called “the king of cancer.” According to the latest WHO data, pancreatic cancer is the seventh cancer in China in 2020 (an estimated 120,000 new people will be added in 2020), and the sixth cancer in death (an estimated 120,000 deaths in 2020).

About 50% of patients with pancreatic ductal adenocarcinoma (PDAC) will develop distant metastases. PDAC metastasis often occurs in the early stages of tumors and is the result of complex interactions between tumor cell autonomous processes and cellular components in the tumor microenvironment.

The oncogene KRAS promotes tumorigenesis, and the inactivation of related key tumor suppressor genes accelerates the malignant progression of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. Approximately 70% of PDAC patients have p53 gene mutations, and approximately 90% of PDAC patients have KRAS gene mutations. The common phenomenon of KRAS and p53 co-mutation in PDAC suggests that there is a potential synergistic mechanism that drives tumor development and metastasis that has yet to be elucidated. An in-depth understanding of the complex interaction between mutant KRAS and mutant p53 will help develop therapies to reverse the malignant progression of tumors.

On April 10, 2021, Michael P. Kim of MD Anderson Cancer Center in the United States published a research paper titled “Oncogenic KRAS recruits an expansive transcriptional network through mutant p53 to drive pancreatic cancer metastasis” in Cancer Discovery.

Mutant KRAS and mutant p53 are the most common mutated genes in pancreatic cancer. The study showed that they interact with CREB1 protein to promote the growth and metastasis of pancreatic cancer. It further revealed that blocking CREB1 in preclinical models can reverse these effects and reduce pancreatic cancer metastasis, providing a new therapeutic target for this deadly cancer.

It is reported that this is also the first study to show how the two main genetic drivers, mutant KRAS and mutant p53, can jointly promote tumor growth and metastasis.

How mutant KRAS and p53 can together promote pancreatic cancer?


In this study, the degree of direct cooperation between KRAS and mutant p53 was explored in order to find a new therapeutic strategy to slow the progression and metastasis of cancer. In order to express the mutant p53R172H (corresponding to the human p53R175H hotspot mutation) only in PDAC, while retaining the wild-type p53 function in all mesenchymal cells, the research team constructed LSL- KrasG12D; p53wmR172H/+; Pdx1-Cre (KPwm/+ C) A mouse, which exhibits the characteristics of tumor aggressiveness and metastasis, indicating that the mutation p53R172H significantly increases PDAC metastasis in vivo.

How mutant KRAS and p53 can together promote pancreatic cancer?


Next, the research team used flow cytometry, RNA-seq, and TFBS computing systems to detect the up-regulated gene promoters in the mutant p53R172H tumors and found that the mutant p53 tumors are related to the transcriptional characteristics of FOXA1. The human PDAC TCGA data set was used to compare the expression of FOXA1 in normal pancreas and PDAC tumors, and it was found that the average expression value of FOXA1 in PDAC patients increased by >7 times, indicating that it is generally up-regulated in pancreatic cancer and is related to prognosis.

How mutant KRAS and p53 can together promote pancreatic cancer?


In order to understand how the mutant p53 interacts with the transcription complex at the FOXA1 promoter to drive its expression, the research team performed genetic and pharmacological inhibition, luciferase dual reporting, and immunocompetence in a set of mouse and human PDAC cell lines. Precipitation and ChIP qPCR experiments showed that oncogenic KRAS mainly mediates the phosphorylation of CREB1S133. Activated CREB1 can enhance the binding of mutant p53 and FOXA1 promoter, leading to activation of the transcription network, while promoting Wnt/β-catenin signal transduction and driving together PDAC transfer.

How mutant KRAS and p53 can together promote pancreatic cancer?


In summary, this study details a new molecular mechanism of pancreatic cancer metastasis, namely, the acquisition of function by mutant p53 to drive PDAC metastasis, which is conditioned by the phosphorylation of CREB1S133, mainly through oncogenic KRAS -Mediated by the RAF-MEK-MAPK pathway. Drug inhibition of CREB1 significantly reduced the expression of FOXA1 and β-catenin, and inhibited PDAC metastasis. This determined a new treatment strategy to disrupt the interaction between mutant KRAS and mutant p53 to delay cancer progression and metastasis.


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