Long noncoding RNAs (lncRNAs) are recently implicated in modifying immunology in colorectal cancer (CRC). Nevertheless, the clinical significance of immune-related lncRNAs remains largely unexplored. In this study, we develope a machine learning-based integrative procedure for constructing a consensus immune-related lncRNA signature (IRLS). IRLS is an independent risk factor for overall survival and displays stable and powerful performance, but only demonstrates limited predictive value for relapse-free survival. Additionally, IRLS possesses distinctly superior accuracy than traditional clinical variables, molecular features, and 109 published signatures. Besides, the high-risk group is sensitive to fluorouracil-based adjuvant chemotherapy, while the low-risk group benefits more from bevacizumab. Notably, the low-risk group displays abundant lymphocyte infiltration, high expression of CD8A and PD-L1, and a response to pembrolizumab. Taken together, IRLS could serve as a robust and promising tool to improve clinical outcomes for individual CRC patients.

Tumor metastasis is the leading cause of death in patients with colorectal cancer (CRC). Circular RNAs (circRNAs) have been shown to be involved in cancer progression. However, the regulatory mechanisms of circRNAs involved in CRC tumor metastasis are currently unknown. Methods: High-throughput sequencing was performed on 6 pairs of CRC and adjacent normal tissues to identify the expression profiles of mRNA and circRNA. circ1662 was assessed by RNA-ISH and IHC of a tissue chip. The function of circ1662 in CRC was evaluated by knocking down or overexpressing circ1662. MeRIP-qPCR, RIP-qPCR, and RNA pull-down were performed to determine the relationship between METTL3, circ1662, and YAP1. Results: A novel circRNA, circ1662, exhibited significantly higher expression in CRC tissues than paired normal tissues. High circ1662 expression was correlated with poor prognosis and tumor depth in patients with CRC. Functionally, circ1662 promoted CRC cell invasion and migration by controlling EMT in vitro and in vivo . Mechanistically, circ1662 directly bound to YAP1 and accelerated its nuclear accumulation to regulate the SMAD3 pathway. Additionally, circ1662 enhanced CRC invasion and migration depending on YAP1 and SMAD3. Interestingly, METTL3 induced circ1662 expression by binding its flanking sequences and installing m6A modifications. Clinically, circ1662 expression strongly correlated with METTL3 and YAP1 protein expression. Moreover, YAP1 expression was negatively correlated with SMAD3 expression. Conclusions: METTL3-induced circ1662 promoted CRC cell invasion and migration by accelerating YAP1 nuclear transport. This result implies that circ1662 is a new prognostic and therapeutic marker for CRC metastasis.

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Summary Background Long non-coding RNAs (lncRNAs) have recently emerged as essential biomarkers of cancer progression. However, studies are limited regarding lncRNAs correlated with recurrence and fluorouracil-based adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC). Methods 1640 stage II/III CRC patients were enrolled from 15 independent datasets and a clinical in-house cohort. 10 prevalent machine learning algorithms were collected and then combined into 76 combinations. 109 published transcriptome signatures were also retrieved. qRT-PCR assay was performed to verify our model. Findings We comprehensively identified 27 stably recurrence-related lncRNAs from multi-center cohorts. According to these lncRNAs, a consensus machine learning-derived lncRNA signature (CMDLncS) that exhibited best power for predicting recurrence risk was determined from 76 kinds of algorithm combinations. A high CMDLncS indicated unfavorable recurrence and mortality rates. CMDLncS not only could work independently of common clinical traits (e.g., AJCC stage) and molecular features (e.g., microsatellite state, KRAS mutation), but also presented dramatically better performance than these variables. qRT-PCR results from 173 patients further verified our in-silico findings and assessed its feasible in different centers. Comparisons of CMDLncS with 109 published transcriptome signatures further demonstrated its predictive superiority. Additionally, patients with high CMDLncS benefited more from fluorouracil-based ACT and were characterized by activation of stromal and epithelial-mesenchymal transition, while patients with low CMDLncS suggested the sensitivity to bevacizumab and displayed enhanced immune activation. Interpretation CMDLncS provides an attractive platform for identifying patient at high risk of recurrence and could optimize precision treatment to improve the clinical outcomes in stage II/III CRC. Funding This study was supported by the National Natural Science Foundation of China (81,972,663); Henan Province Young and Middle‐Aged Health Science and Technology Innovation Talent Project (YXKC2020037); and Henan Provincial Health Commission Joint Youth Project (SB201902014).

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.