New research reveals an important mechanism of heat-induced squamous cell carcinoma of the esophagus

Thermal stress involved in TRPV2 promotes tumorigenesis in esophageal squamous cell carcinoma. Courtesy of the research team

Recently, the British Journal of Cancer and Cancer Research UK jointly published the latest research results of Li Zhiyuan’s team, a researcher at the Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences. They not only revealed the important role played by transient receptor potential vanilloid 2 (TRPV2) channel in the occurrence and development of esophageal squamous cell carcinoma, but also proposed a new direction for the prevention and treatment of esophageal squamous cell carcinoma.

The study found for the first time that repeated heating or agonist action of heat-sensitive TRPV2 can activate the HSP70/27 and PI3K/Akt/mTOR signaling pathways, which can significantly promote the malignant behavior of esophageal squamous cell carcinoma cells in in vitro experiments, and significantly promote the tumorization and spread of esophageal squamous cell carcinoma in vivo.

Esophageal cancer is one of the world’s most frequent malignant tumors in China, according to the 2020 international cancer data, more than half of the world’s new esophageal cancer is concentrated in China, and its incidence and mortality rate in China are ranked 5th and 4th in all malignant tumors, which seriously threatens the life and health of Chinese residents. Esophageal cancer mainly includes adenocarcinoma and squamous cell carcinoma (ESCC), and more than 90% of esophageal cancer in China is squamous cell carcinoma. Most of the esophageal cancers have progressed to the middle and advanced stages when they are diagnosed, and the overall 5-year survival rate of patients is less than 20%.

It is known that the onset and progression of esophageal cancer is related to polygenic abnormalities, and external environmental factors, especially high-temperature diet, are considered to be one of the main risk factors causing esophageal squamous cell carcinoma, and high-temperature diet often causes the esophageal mucosa to undergo frequent and repeated thermal stimulation, resulting in an increased risk of functional variation of esophageal mucosal epithelial cells. In fact, hyperpyretic stimulation has been listed by the International Agency for Research on Cancer as one of the class II causes of esophageal cancer, however, little is known about its intrinsic molecular mechanisms.

To this end, based on years of research on transient receptor potential ion channels (TRP), Li Zhiyuan’s team first detected the expression and function of the thermological TRPV in human esophageal squamous epithelial cells, and found that compared with non-tumor tissues, the expression of TRPV2 in ESCC cells and clinical ESCC samples was significantly upregulated, and calcium imaging experiments confirmed that its functional activity was correspondingly enhanced.

Further studies have found that after brief and frequent stimulation of ESCC cells with heat (54 °C) to activate the TRPV2 channel, malignant cell behaviors such as proliferation, invasion and pro-angiogenesis of ESCC cells can be significantly enhanced in in vitro experiments, while in vivo experiments can significantly promote subcutaneous tumorigenesis and tail vein injection tumor metastasis in nude mice. Similar results were achieved after the use of the TRPV2-specific activator O1821 on ESCC cells. Conversely, the oncogenic effect of ESCC was significantly weakened by the application of the TRPV2 antagonist Tranilast or the knockout of the TRPV2 gene in ESCC cells by CRISPR-Cas9 method. In addition, after overexpressing TRPV2 in non-neoplastic esophageal squamous cells NE2, transient and frequent action on NE2 cells at heat (54 °C) and O1821 can significantly promote the proliferation of NE2, making it appear invasive and tumoried under the skin of nude mice, indicating that overexpressed activated TRPV2 can turn non-tumor cells to tumorization.

Mechanically, TRPV2 upregulates heat shock factor 1 (HSF1) of cells and promotes transcriptional expression of heat shock proteins 70 and 27 (HSP70/27) after ESCC cells are activated by heat stress, thereby promoting tumorigenesis of ESCC; At the same time, PI3K is significantly activated in this process, which activates its downstream signaling protein PDK1, and then PDK1 upregulates the function of the target proteins AKT1 and mTORC1, and conversely, the negative regulator protein PTEN of PI3K is down-regulated and inhibited, indicating that the PI3K signal is amplified by PTEN, thereby significantly promoting the tumorigenesis and aggressiveness of ESCC. The activated TRPV2 also upregulated the phosphorylation levels of Akt proteins at the S473 and T308 sites, while p-mTOR (S2448) and effector protein phosphorylation levels p-p70S6K and p-4EBP1 (S65) were increased accordingly. The application of Tranilast or knockout of the TRPV2 gene inhibits these effects.

The study also found that pan-PI3K/mTOR kinase inhibitors VS5584 and Oroxin B significantly inhibited the proliferation of TRPV2 overactivated ESCC cells, and the combination of the two with Tranillast further weakened the proliferation ability of ESCC cells, suggesting that Tranilast in combination with pan-PI3K/mTOR inhibitors may be available for the treatment of ESCC. Multifactorial survival analysis suggests that TPRV2 hyperexpression is an independent factor in poor prognosis in ESCC patients, suggesting that TRPV2 is expected to become a biomarker and a new therapeutic target for poor ESCC prognosis.

Notably, the activation temperature of the TRPV2 channel found in the study is 54 °C, which is lower than the dietary temperature in many people and also far lower than the high temperature diet risk temperature recommended by the International Agency for Research on Cancer (65 °C), so the study proposes a new direction for the prevention and treatment of esophageal squamous cell carcinoma.

Dr. Huang Rongqi of Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, is the first author of the paper, and Researcher Li Zhiyuan is the corresponding author. The research work has been supported by the Li Ka Shing School of Medicine of the University of Hong Kong, the Second Xiangya Hospital of Central South University and the Hunan Provincial Cancer Hospital, and has also been assisted by Li Peng, Lai Liangxue, researchers of the Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences.

The research was funded by the National Natural Science Foundation of China, Guangdong Province, and the Frontier Research Project of the Bio-Island Laboratory. (Source: China Science Daily Zhu Hanbin)

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