Metastasis is an important factor contributing to poor prognosis in patients with gastric cancer; yet, the molecular mechanism leading to this cell behavior is still not well understood. In this study, we explored the role of cysteine protease inhibitor SN (Cystatin SN, CST1) in promoting gastric cancer metastasis. We hypothesized that CST1 could regulate gastric cancer progression by regulating GPX4 and ferroptosis. Whole transcriptome sequencing suggested that the expression of CST1 was significantly increased in metastatic cancer, and high CST1 expression was correlated with a worse prognosis. Our data further confirmed that the overexpression of CST1 may significantly promote the migration and invasion of gastric cancer cells in vitro and enhance liver, lung, and peritoneal metastasis of gastric cancer in nude mice. Meanwhile, high expression of CST1 promoted the epithelial-mesenchymal transition (EMT) of gastric cancer cells. Mechanistically, a co-immunoprecipitation experiment combined with mass spectrometry analysis confirmed that CST1 could interact with GPX4, a key protein regulating ferroptosis. CST1 relieves GPX4 ubiquitination modification by recruiting OTUB1, improving GPX4 protein stability and reducing intracellular reactive oxygen species (ROS), thereby inhibiting ferroptosis and, in turn, promoting gastric cancer metastasis. Moreover, clinical data suggested that CST1 is significantly increased in peripheral blood and ascites of gastric cancer patients with metastasis; multivariate Cox regression model analysis showed that CST1 was an independent risk factor for the prognosis of gastric cancer patients. Overall, our results elucidated a critical pathway through which high CST1 expression protects gastric cancer cells from undergoing ferroptosis, thus promoting its progression and metastasis. CST1 may be used as a new oncological marker and potential therapeutic target for gastric cancer metastasis.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related death worldwide. China accounts for over half of the new cases and deaths. Diagnostic imprecision and a lack of complimentary molecular biomarkers are partially responsible for this lack of progress. Herein, serum‐derived exosomal microRNA (miRNA) profiling was performed on 80 patients which histologically confirmed HCC and 30 normal controls. A classification of 8 exosomal miRNAs had biologically and statistically significant differences between HCC and normal serum samples, including miR‐122, miR‐125b, miR‐145, miR‐192, miR‐194, miR‐29a, miR‐17‐5p, and miR‐106a. Online algorithm showed strong independent classification accuracy (area under the curve) reached 0.535 to 0.850, separately. The significant correlation between serum exosomal miRNAs and tumor size was observed. In addition, the survival difference of HCC patients with high or low exosomal miR‐106a was statistically significant using Kaplan‐Meier analysis. Besides, we also measured the proliferation and invasion ability of HCC cells following exosomal miR‐106a mimics or inhibitor treatment. After prediction with algorithms, mitogen‐activated protein kinase and c‐Jun N‐terminal kinase pathways were identified associated with miR‐106a’s function. In summary, differentially expressed serum exosomal miRNAs can be helpful for diagnostic and prognostic of HCC.

Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors with high incidence and mortality rate. Precision and effective biomarkers are therefore urgently needed for the early diagnosis and prognostic estimation. MicroRNAs (miRNAs) are important regulators which play functions in various cellular processes and biological activities. Accumulating evidence indicated that the abnormal expression of miRNAs are closely associated with HCC initiation and progression. Recently, many biomarker miRNAs for HCC have been identified from blood or tissues samples, however, the universality and specificity on clinicopathological features of them are less investigated. In this review, we comprehensively surveyed and compared the diagnostic, prognostic, and therapeutic roles of HCC biomarker miRNAs in blood and tissues based on the cancer hallmarks, etiological factors as well as ethnic groups, which will be helpful to the understanding of the pathogenesis of biomarker miRNAs in HCC development and further provide accurate clinical decisions for HCC diagnosis and treatment.

Noncoding RNAs have been verified to regulate the infiltration of macrophages to accelerate tumor biological progression, however the regulation of macrophages by circular RNAs in hepatocellular carcinoma (HCC) remains unresolved. Using high‐throughput RNA sequencing, we demonstrated that hsa_circ_0003410 was clearly upregulated in HCC. 5‐Ethynyl‐2′‐deoxyuridine and transwell assays showed that hsa_circ_0003410 facilitated the proliferation and migration of HCC cells in vitro. We knocked down the expression of hsa_circ_0003410 in HepG2 cells and performed next‐generation sequencing to determine possible target genes of hsa_circ_0003410. Kyoto Encyclopedia of Genes and Genomes analysis revealed that different genes were mainly enriched in immune‐related pathways. Mechanistically, we identified CCL5 as the target gene of hsa_circ_0003410. RNA‐FISH showed the co‐expression of hsa_circ_0003410 and CCL5. Western blot and ELISA also verified that hsa_circ_0003410 could upregulate the expression of CCL5 protein. Flow cytometry and immunofluorescence assays indicated that CCL5 activated and recruited M2 macrophages and increased the ratio of M2/M1 macrophages to promote the progression of HCC. Animal experiments in vitro also confirmed our results. Taken together, our experiments revealed that noncoding RNAs play a critical role in the HCC microenvironment and can be considered as markers for the diagnosis and prognosis of HCC.

Circular RNA (circRNA) plays an essential role in the development and progression of various cancers. However, the functions and mechanisms of circRNA in colorectal liver metastasis have not been fully elucidated. We performed circRNA microarray analysis to screen differentially expressed circRNA in the pathology of colorectal liver metastasis. Quantitative real‐time PCR was used to detect the expression of hsa_circ_102049 (circ102049) in colorectal cancer (CRC) samples. CRC cells were transfected with circ102049 overexpression vector or small interfering (si)RNA to assess the effects of circ102049 in vitro. Bioinformatics analysis, fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull‐down and luciferase reporter assays were conducted to confirm the relationship of circ102049, miR‐761, miR‐192‐3p and FRAS1. The mechanism by which circ102049 recruits and distributes DGCR8 protein in the cytoplasm was also investigated. We found that circ102049 was highly expressed in primary CRC tumors with liver metastasis and closely correlated with the prognosis of patients with CRC. Circ102049 significantly enhanced the adhesion, migration and invasion abilities of CRC cells, and promoted CRC progression via a micro (mi)R‐761/miR‐192‐3p‐FRAS1‐dependent mechanism. Notably, due to the distribution of DGCR8 protein, circ102049 may also indirectly reduce the levels of mature miR‐761 and miR‐192‐3p in the cytoplasm. In addition, the role of circ102049 in promoting colorectal liver metastasis was confirmed in vivo. Our findings provide new evidence that circ102049 may be a potential prognostic factor in CRC, and that the circ102049‐miR‐761/miR‐192‐3p–FRAS1 axis may be an anti‐metastatic target for CRC patients.