A miR-375/YAP axis regulates neuroendocrine differentiation and tumorigenesis in lung carcinoid cells

Abstract

Lung carcinoids are variably aggressive and mechanistically understudied neuroendocrine neoplasms (NENs). Here, we identified and elucidated the function of a miR-375/yes-associated protein (YAP) axis in lung carcinoid (H727) cells. miR-375 and YAP are respectively high and low expressed in wild-type H727 cells. Following lentiviral CRISPR/Cas9-mediated miR-375 depletion, we identified distinct transcriptomic changes including dramatic YAP upregulation. We also observed a significant decrease in neuroendocrine differentiation and substantial reductions in cell proliferation, transformation, and tumor growth in cell culture and xenograft mouse disease models. Similarly, YAP overexpression resulted in distinct and partially overlapping transcriptomic changes, phenocopying the effects of miR-375 depletion in the same models as above. Transient YAP knockdown in miR-375-depleted cells reversed the effects of miR-375 on neuroendocrine differentiation and cell proliferation. Pathways analysis and confirmatory real-time PCR studies of shared dysregulated target genes indicate that this axis controls neuroendocrine related functions such as neural differentiation, exocytosis, and secretion. Taken together, we provide compelling evidence that a miR-375/YAP axis is a critical mediator of neuroendocrine differentiation and tumorigenesis in lung carcinoid cells.

Intermittent Hypoxia Increased the Expression of DBH and PNMT in Neuroblastoma Cells via MicroRNA-375-Mediated Mechanism

“…They affect the stability of their target mRNAs, resulting in changes in the amount of target mRNA, which is one of the mechanisms associated with post-transcriptional regulation. To date, a number of studies concerning the role of miR-375 have been reported to be influenced in normal pancreatic genesis [ 28 ], the proinflammatory macrophage response [ 29 ], pituitary prolactin synthesis [ 30 ], neuroendocrine differentiation and tumorigenesis in lung carcinoid cells [ 31 ], inhibition in proliferation and invasion of nasopharyngeal carcinomas [ 32 ], and inhibition in the proliferation, migration, and invasion of esophageal squamous cell carcinomas [ 33 ]. Several such studies have indicated that miRNAs are involved in the regulation of many biological processes (migration, metastasis, cell proliferation, apoptosis, chemosensitivity, etc.)…”

The uprise of RNA biology in neuroendocrine neoplasms: altered splicing and RNA species unveil translational opportunities

“…In atypical carcinoids, hsa-let-7f-5p is overexpressed, showing an inverse correlation with its predicted target, HMGA2 [ 88 ]. In pulmonary carcinoids, miR-375 is highly expressed, which seems to downregulate YAP expression, inducing neuroendocrine differentiation and cell proliferation [ 79 ]. In SCLC, miR-518d-5p is known to be a negative regulator of DLL3 mediated cell proliferation and migration [ 89 ].…”

Prognostic significance of YAP1 expression and its association with neuroendocrine markers in resected pulmonary large cell neuroendocrine carcinoma (LCNEC)

“…Yang et al. found that the miR-375/YAP axis is an important mediator of neuroendocrine differentiation in lung cancer [28] . Besides, studies have shown that the expression of the neuroendocrine marker RAB3A can be induced by knocking down YAP1 12 .…”