MiR-103a-3p promotes tumour glycolysis in colorectal cancer via hippo/YAP1/HIF1A axis

Abstract

Background Glycolysis plays an essential role in the growth and metastasis of solid cancer and has received increasing attention in recent years. However, the complex regulatory mechanisms of tumour glycolysis remain elusive. This study aimed to explore the molecular effect and mechanism of the noncoding RNA miR-103a-3p on glycolysis in colorectal cancer (CRC). Methods We explored the effects of miR-103a-3p on glycolysis and the biological functions of CRC cells in vitro and in vivo. Furthermore, we investigated whether miR-103a-3p regulates HIF1A expression through the Hippo/YAP1 pathway, and evaluated the role of the miR-103a-3p-LATS2/SAV1-YAP1-HIF1A axis in promoting glycolysis and angiogenesis in CRC cells and contributed to invasion and metastasis of CRC cells. Results We found that miR-103a-3p was highly expressed in CRC tissues and cell lines compared with matched controls and the high expression of miR-103a-3p was associated with poor patient prognosis. Under hypoxic conditions, a high level of miR-103a-3p promoted the proliferation, invasion, migration, angiogenesis and glycolysis of CRC cells. Moreover, miR-103a-3p knockdown inhibited the growth, proliferation, and glycolysis of CRC cells and promoted the Hippo-YAP1 signalling pathway in nude mice in a xenograft model. Here, we demonstrated that miR-103a-3p could directly target LATS2 and SAV1. Subsequently, we verified that TEAD1, a transcriptional coactivator of Yes-associated protein 1 (YAP1), directly bound to the HIF1A promoter region and the YAP1 and TEAD1 proteins co-regulated the expression of HIF1A, thus promoting tumour glycolysis. Conclusions MiR-103a-3p, which is highly expressed in CRC cells, promotes HIF1A expression by targeting the core molecules LATS2 and SAV1 of the Hippo/YAP1 pathway, contributing to enhanced proliferation, invasion, migration, glycolysis and angiogenesis in CRC. Our study revealed the functional mechanisms of miR-103a-3p/YAP1/HIF1A axis in CRC glycolysis, which would provide potential intervention targets for molecular targeted therapy of CRC.

METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

“…The depletion of CRB3 can inhibit the Hippo pathway and lead to increased nuclear localization of YAP [ 30 , 31 , 43 ]. The Hippo pathway plays a crucial role in regulating CRC progression [ 44 – 47 ]. In the present study, we also observed that CRB3 knockdown inhibited the Hippo pathway and increased the nuclear localization of YAP, suggesting that CRB3 regulates CRC progression through the Hippo pathway.…”

Significance of TEAD Family in Diagnosis, Prognosis and Immune Response for Ovarian Serous Carcinoma

“…22,23 TEAD1 could directly integrate with the hypoxiainducible factor-1A (HIF-1A) promoter region and regulate the expression of HIF1A, facilitating the tumor glycolysis. 24,25 TEAD2 was significantly upregulated in hepatocellular carcinoma (HCC) and the higher expression was associated with poor OS time of HCC. 26,27 In addition, TEAD3 could promote the proliferation of gastric cancer cell line MKN-28 through increasing SLC35B4 expression.…”

MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p

“…If the pathway is blocked or inactivated, unphosphorylated YAP/TAZ may enter the nucleus from the cytoplasm, and combine with TEADs to promote gene transcription, induce cell transformation, and enhance the cell proliferation, invasion, and metastasis [ 31 ]. The abnormal regulation of Hippo signaling pathway is associated with the occurrence and development of diverse types of cancer, such as colorectal cancer [ 32 ], gastric cancer [ 33 ], breast cancer [ 34 ], and MPM [ 35 ].…”