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Accurate risk stratification for patients with stage II/III colon cancer is pivotal for postoperative treatment decisions. Here, we aimed to identify and validate a circRNA‐based signature that could improve postoperative prognostic stratification for these patients. In current retrospective analysis, we included 667 patients with R0 resected stage II/III colon cancer. Using RNA‐seq analysis of 20 paired frozen tissues collected postoperation, we profiled differential circRNA expression between patients with and without recurrence, followed by quantitative validation. With clinical information, we generated a four‐circRNA‐based cirScore to classify patients into high‐risk and low‐risk groups in the training cohort. The patients with high cirScores in the training cohort had a shorter disease‐free survival (DFS) and overall survival (OS) than patients with low cirScores. The prognostic capacity of the classifier was validated in the internal and external cohorts. Loss‐of‐function assays indicated that the selected circRNAs played functional roles in colon cancer progression. Overall, our four‐circRNA‐based classifier is a reliable prognostic tool for postoperative disease recurrence in patients with stage II/III colon cancer.

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Even though ER-positive, HER2-negative breast tumors represent a subset of breast cancers with a better clinical outcome, approximately 12.7 % of patients in this subgroup ultimately develop cancer-related mortality. Recent studies had confirmed that hypoxia-induced autophagy-related gene Beclin 1 expression might be important for disease progression and be correlated with patient outcome in several tumors. Here, we examined the autophagic Beclin 1 and hypoxic HIF-1α levels in 378 ER-positive, HER2-negative breast cancer patients by immunohistochemistry using tissue microarray. We found that Beclin 1 was highly expressed in normal mammary gland epithelia. In contrast, it was either not expressed or only moderately expressed in 78.0 % of breast adenocarcinoma tissue. Compared to the subset overexpressing Beclin 1, the subset in which Beclin 1 levels were reduced had a poor 5-year overall survival rate (OS, 85.1 % vs. 94.1 %, P = 0.005) and a poor distant metastasis-free survival (DMFS, 79.1 % vs. 89.3 %, P = 0.037). Cox multivariate analysis confirmed that Beclin 1 was indeed an independent prognostic factor for OS and DMFS. Additionally, Beclin 1 positively correlated with HIF-1α expression (r = 0.206, P < 0.001). Importantly, among patients with HIF-1α overexpression, low levels of Beclin 1 predicted a worse OS. Our study confirmed that deficiency of Beclin 1 was a negative prognostic factor for OS and DMFS in ER-positive, HER2-negative breast cancer. The combination of Beclin 1 and HIF-1α refined the risk definition of the patient subset and provided a novel way to identify those with a high risk of relapse.

Autophagy can be tumor suppressive as well as promotive in regulation of tumorigenesis and disease progression. Accordingly, the prognostic significance of autophagy key regulator Beclin 1 was varied among different tumors. Here, we detected the clinicopathological and prognostic effect of Beclin 1 in the subtypes of intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). Beclin 1 expression level was detected by immunohistochemistry staining in 106 ICC and 74 ECC patients. We found that Beclin 1 was lowly expressed in 126 (70%) cholangiocarcinoma patients, consist of 72 ICC and 54 ECC. Moreover, the cholangiocarcinoma patients with lymph node metastasis (N1) had a lower Beclin 1 level than that of N0 subgroup (P=0.012). However, we did not detect any correlations between Beclin 1 and other clinicopathological features, including tumor subtypes, vascular invasion, HBV infection, liver cirrhosis, cholecystolithiasis and TNM stage. Survival analysis showed that, compared with the high expression subset, Beclin 1 low expression was correlated with a poorer 3-year progression-free survival (PFS, 69.1% VS 46.8%, P=041) for cholangiocarcinoma. Importantly, our stratified univariate and multivariate analysis confirmed that Beclin 1 lowly expressed ICC had an inferior PFS as well as overall survival than ECC, particularly than that of Beclin 1 highly expressed ECC patients. Thus, our study demonstrated that Beclin 1low expression, correlated with lymph node metastasis, and might be a negative prognostic biomarker for cholangiocarcinoma. Combined Beclin 1 level with the anatomical location might lead to refined prognosis for the subtypes of ICC and ECC.

Arginine methylation is an important posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs). However, the role of PRMTs in colorectal cancer (CRC) progression is not well understood. Here we report that non-POU domain-containing octamer-binding protein (NONO) is overexpressed in CRC tissue and is a potential marker for poor prognosis in CRC patients. NONO silencing resulted in decreased proliferation, migration, and invasion of CRC cells, whereas overexpression had the opposite effect. In a xenograft model, tumors derived from NONO-deficient CRC cells were smaller than those derived from wild-type (WT) cells, and PRMT1 inhibition blocked CRC xenograft progression. A mass spectrometry analysis indicated that NONO is a substrate of PRMT1. R251 of NONO was asymmetrically dimethylated by PRMT1 in vitro and in vivo. Compared to NONO WT cells, NONO R251K mutant-expressing CRC cells showed reduced proliferation, migration, and invasion, and PRMT1 knockdown or pharmacological inhibition abrogated the malignant phenotype associated with NONO asymmetric dimethylation in both KRAS WT and mutant CRC cells. Compared to adjacent normal tissue, PRMT1 was highly expressed in the CRC zone in clinical specimens, which was correlated with poor overall survival in patients with locally advanced CRC. These results demonstrate that PRMT1-mediated methylation of NONO at R251 promotes CRC growth and metastasis, and suggest that PRMT1 inhibition may be an effective therapeutic strategy for CRC treatment regardless of KRAS mutation status.

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