Trop-1/EpCAM Thr115是癌细胞增殖的一种新型诱导因子,并驱动COVID-19中的过度增殖性肺损伤

SARS-CoV-2 infection triggers an acute reaction that can severely impair lung function. However, the underlying molecular processes are poorly understood. Our findings showed that the pM115T polymorphism of TROP1/EPCAM associates with COVID-19 severity. The p.M115T polymorphism of TROP1/EPCAM gene had been associated with higher frequency of early-onset breast cancer. However, the functional role of Thr115 Trop-1/EpCAM remained essentially unknown. We explored whether the Thr115 Trop-1/EpCAM acts as a driver of cell proliferation and whether this can play a role in lung pathology / lesion repair in COVID-19 patients. TROP1/EPCAM knockout embryonic stem cells showed altered proliferation. The Trop-1/EpCAM Thr115 allele was found to drive hyperproliferative capacity in murine fibrosarcoma cells, whereas the Met115 allele did not. A corresponding role was assessed in human colon cancer cells, through CRISPR-Cas9 ablation of the endogenous TROP1/EPCAM and comparative transfection of Trop-1/EpCAM Thr115 or Met115 alleles. The Trop-1/EpCAM Thr115 was shown to induce colon cancer cell hyperproliferation, whereas the Met115 allele was devoid of cell growth-driving capacity. Trop-1/EpCAM Thr115 was correspondingly shown to drive the main pathological mechanisms that lead to oxygen-exchange impairment in COVID-19. Morphometric analysis of autoptic lung samples, immunohistochemistry analysis for Trop-1/EpCAM expression, Ki67 proliferation index and comparative computational image analysis were utilized to analyze SARS-CoV-2-infected lungs at autopsy. This showed hyperproliferation of Thr115 Trop-1/EpCAM+ epithelial cells over the alveolar epithelium damaged by the infection. This correlated with Thr115 Trop-1/EpCAM+ inflammatory cells hyperproliferation and alveolar hyaline membrane formation. These multi-layered barriers were computed to reduce oxygen diffusion by up to 100-fold versus normal alveolar structures, with a critical pathological impact. Our findings identify a novel mechanism of induction of cancer cell proliferation by a polymorphic, wild-type Trop-1/EpCAM. A corresponding process was shown to operate in COVID-19 patients, causing an aberrant lung repair, via Trop-1/EpCAM Thr115-induced cell overproliferation. These findings indicate unexpected parallels between inflammation-driven wound-repair in the lungs and cancer cell hyperproliferation as driven by via Trop-1/EpCAM Thr115. Novel diagnostic/ prognostic/ therapeutic opportunities are suggested in Thr115 Trop-1/EpCAM+ COVID-19 patients, and in Thr115 Trop-1/EpCAM+ cancer patients. Acknowledgments: Grant PNRR - Tuscany Health Ecosystem (THE), Next Generation EU, Missione 4, Componente 2, Inv. 1.5, CUP B63C22000680007.