Long non-coding RNA CCDC183-AS1 acts AS a miR-589-5p sponge to promote the progression of hepatocellular carcinoma through regulating SKP1 expression.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common type of malignant human cancer with high morbidity and poor prognosis, causing numerous deaths per year worldwide. Growing evidence has been demonstrated that long non-coding RNAs (lncRNAs) are closely associated with hepatocarcinogenesis and metastasis. However, the roles, functions, and working mechanisms of most lncRNAs in HCC remain poorly defined. METHODS: Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression level of CCDC183-AS1 in HCC tissues and cell lines. Cell proliferation, migration and invasion ability were evaluated by CCK-8 and transwell assay, respectively. Animal experiments were used to explore the role of CCDC183-AS1 and miR-589-5p in vivo. Bioinformatic analysis, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to confirm the regulatory relationship between CCDC183-AS1, miR-589-5p and SKP1. RESULTS: Significantly upregulated expression of CCDC183-AS1 was observed in both HCC tissues and cell lines. HCC patients with higher expression of CCDC183-AS1 had a poorer overall survival rate. Functionally, overexpression of CCDC183-AS1 markedly promoted HCC cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo, whereas the downregulation of CCDC183-AS1 exerted opposite effects. MiR-589-5p inhibitor counteracted the proliferation, migration and invasion inhibitory effects induced by CCDC183-AS1 silencing. Mechanistically, CCDC183-AS1 acted as a ceRNA through sponging miR-589-5p to offset its inhibitory effect on the target gene SKP1, then promoted the tumorigenesis of HCC. CONCLUSIONS: CCDC183-AS1 functions as an oncogene to promote HCC progression through the CCDC183-AS1/miR-589-5p/SKP1 axis. Our study provided a novel potential therapeutic target for HCC patients.

Microenvironment characterization and multi-omics signatures related to prognosis and immunotherapy response of hepatocellular carcinoma.

BACKGROUND: Immune cell infiltration in the tumor microenvironment (TME) affects tumor initiation, patients' prognosis and immunotherapy strategies. However, their roles and interactions with genomics and molecular processes in hepatocellular carcinoma (HCC) still have not been systematically evaluated. METHODS: We performed unsupervised clustering of total 1000 HCC samples including discovery and validation group from available public datasets. Immune heterogeneity of each subtype was explored by multi-dimension analysis. And a support vector machine (SVM) model based on multi-omics signatures was trained and tested. Finally, we performed immunohistochemistry to verify the immune role of signatures. RESULTS: We defined three immune subtypes in HCC, with diverse clinical, molecular, and genomic characteristics. Cluster1 had worse prognosis, better anti-tumor characteristics and highest immune scores, but also accompanied by immunosuppression and T cell dysfunction. Meanwhile, a better anti-PD1/CTLA4 immunotherapeutic response was predicted in cluster1. Cluster2 was enriched in TAM-M2 and stromal cells, indicating immunosuppression. Cluster3, with better prognosis, had lowest CD8 T cell but highest immune resting cells. Further, based on genomic signatures, we developed an SVM classifier to identify the patient's immunological status, which was divided into Type A and Type B, in which Type A had poorer prognosis, higher T cell dysfunction despite higher T cell infiltration, and had better immunotherapeutic response. At the same time, MMP9 may be a potential predictor of the immune characteristics and immunotherapeutic response in HCC. CONCLUSIONS: Our work demonstrated 3 immune clusters with different features. More importantly, multi-omics signatures, such as MMP9 was identified based on three clusters to help us recognize patients with different prognosis and responses to immunotherapy in HCC. This study could further reveal the immune status of HCC and provide potential predictors for immune checkpoint treatment response.

Multicenter analysis of long-term oncologic outcomes of hepatectomy for elderly patients with hepatocellular carcinoma.

BACKGROUND: Aging of the population and prolonged life expectancy have significantly increased the number of elderly patients undergoing hepatectomy for hepatocellular carcinoma (HCC). However, potential benefits, especially long-term oncologic outcomes of hepatectomy for elderly patients with HCC remain unclear. METHOD: Patients treated with curative-intent hepatectomy for HCC in 8 Chinese hospitals were enrolled. Patients were divided into the elderly (≥70 years old) and younger (<70 years old) groups. Overall survival (OS), cancer-specific survival (CSS), and time-to-recurrence (TTR) were compared. Risk factors of CSS and TTR were evaluated by univariable and multivariable competing-risk regression analyses. RESULTS: Of 2134 patients, 259 (12.1%) and 1875 (87.9%) were elderly and younger aged, respectively. Postoperative 30-day and 90-day mortality was comparable among elderly and younger patients. Compared with younger patients, the elderly had a worse 5-year OS (49.4% vs. 55.3%, P = 0.032), yet a better 5-year CCS (74.5% vs. 61.0%, P = 0.005) and a lower 5-year TTR (33.7% vs. 44.9%, P < 0.001), respectively. Multivariable analyses identified that elder age was independently associated with more favorable CSS (HR 0.74, 95%CI 0.58-0.90, P = 0.011) and TTR (0.69, 0.53-0.88, P < 0.001) but was not associated with OS (P = 0.136). CONCLUSIONS: Age by itself is not a contraindication to surgery, and selected elderly patients with HCC can benefit from hepatectomy. Compared with younger patients, elderly patients have noninferior oncologic outcomes following hepatectomy for HCC.

Incomplete radiofrequency ablation provokes colorectal cancer liver metastases through heat shock response by PKCα/Fra-1 pathway.

OBJECTIVE: Incomplete radiofrequency ablation (ICR) has been proposed as a major cause of recurrence in the treatment of hepatic metastatic tumors. We tried to determine the mechanisms of this progression in colorectal cancer (CRC) liver metastasis (CRLMs). METHODS: We have established a mouse model of radiofrequency ablation (RFA) therapy to demonstrate increased risk of recurrence of CRLMs with ICR. Here we focused on heat shock-induced CRC malignancy. Sub-lethal heat shock (HS) in CRC cell lines provoked cell growth, invasion, and tumor initiation in vitro and in vivo. RESULTS: We found that Fra-1, which lies downstream of PKCα-ERK1/2 signaling, was significantly increased by HS compared with the untreated CRC cells. Silencing Fra-1 reversed the tumor promoting effects of HS. Furthermore, proliferation and tumor initiation inducer c-Myc, together with tumor invasion inducer matrix-metalloprotase 1 (MMP-1) expression were up-regulated by AP-1/Fra-1 induced genes transcription. CONCLUSIONS: Our study demonstrated that ICR generated HS induces CRC malignancy by targeting Fra-1, which could be a potential prognostic marker and a promising therapeutic strategy to prevent disease recurrence after radiofrequency ablation treatment.

Cancer cell-derived immunoglobulin G activates platelets by binding to platelet FcγRIIa.

Tumor-associated thrombosis is the second leading risk factor for cancer patient death, and platelets activity is abnormal in cancer patients. Discovering the mechanism of platelet activation and providing effective targets for therapy are urgently needed. Cancer cell- derived IgG has been reported to regulate development of tumors. However, studies on the functions of cancer cell-derived IgG are quite limited. Here we investigated the potential role of cancer cell-derived IgG in platelet activation. We detected the expression of CD62P on platelets by flow cytometry and analyzed platelet function by platelets aggregation and ATP release. The content of IgG in cancer cell supernatants was detected by enzyme-linked immune sorbent assay. The distribution of cancer-derived IgG in cancer cells was analyzed by immunofluorescence assay. Western blot was performed to quantify the relative expression of FcγRIIa, syk, PLCγ2. The interaction between cancer cell-derived IgG and platelet FcγRIIa was analyzed by co-immunoprecipitation. The results showed that higher levels of CD62P were observed in cancer patients' platelets compared with that of healthy volunteers. Cancer cell culture supernatants increased platelet CD62P and PAC-1 expression, sensitive platelet aggregation and ATP release in response to agonists, while blocking FcγRIIa or knocking down IgG reduced the activation of platelets. Coimmunoprecipitation results showed that cancer cell-derived IgG interacted directly with platelet FcγRIIa. In addition, platelet FcγRIIa was highly expressed in liver cancer patients. In summary, cancer cell-derived IgG interacted directly with FcγRIIa and activated platelets; targeting this interaction may be an approach to prevent and treat tumor-associated thrombosis.

Benefits of Splenectomy and Curative Treatments for Patients with Hepatocellular Carcinoma and Portal Hypertension: a Retrospective Study.

BACKGROUND: We aimed to explore the benefit of splenectomy combined with curative treatments (liver resection or local ablation) for patients with hepatocellular carcinoma and portal hypertension. METHODS: The records of 239 patients with hepatocellular carcinoma and portal hypertension undergoing either splenectomy combined with liver resection or local ablation were reviewed retrospectively. Perioperative complications and survival outcome were evaluated, and liver function 1 year later was reassessed according to the Child score. RESULTS: The post-hepatectomy liver failure rates and 30-day mortality were 3.3% and 2.1%, respectively. The 1-, 3-, and 5-year overall survival rates were 95.1%, 73%, and 47.5% for patients with Child grade A and 92.2%, 51.2%, and 19.8% for Child grade B, respectively. The median survival time for patients with Child scores of 5, 6, 7, 8, and 9 were 61.5, 51.3, 44.8, 33.7, and 23.4 months, respectively. After multivariable analysis, tumor size, tumor number, post-hepatectomy liver failure, and Child score were independent risk factors for overall survival. Liver function was converted to Child grade A in 98 of 101 patients (97%) who had preoperative Child grade B 1 year after splenectomy. CONCLUSION: Patients with hepatocellular carcinoma and portal hypertension can benefit from splenectomy combined with curative treatments, especially those with Child scores of 5, 6, and 7. Liver function improved significantly 1 year after splenectomy in patients with preoperative Child grade B.

Improved survival following splenectomy combined with curative treatments for hepatocellular carcinoma in Child B patients: A propensity score matching study.

AIMS: To explore the benefits of curative treatments (liver resection or local ablation) combined with splenectomy for patients with hepatocellular carcinoma (HCC) and Child grade B liver function. METHODS: We reviewed 245 patients with Child grade B liver function who underwent treatment with curative intent for HCC. Among these patients, 116 patients underwent curative treatment combined with splenectomy (the splenectomy group); the other 129 patients only underwent curative treatment (the non-splenectomy group). A one-to-one matching produced 95 paired patients, perioperative and oncological outcomes were compared, and liver function changes were reassessed 1 year later. RESULTS: The perioperative liver failure rates were 7.4% and 6.3% (P = 1.000) and the 90-day mortality was 4.2% and 6.3% (P = 0.747) in the splenectomy group and non-splenectomy group, respectively. The 1-, 3-, and 5-year overall survival rates were remarkably greater in the splenectomy group than in the non-splenectomy group (92.6% vs. 79.8%, 53.4% vs. 34.7%, and 19.9% vs. 11.0%, respectively; P = 0.004). In the univariate and multivariate analyses, splenectomy was identified as a protective factor for long-term survival. The proportion of patients whose liver function improved to Child A 1 year after surgery was also higher in the splenectomy group than in the non-splenectomy group (95.4% vs. 83.3%; P = 0.048). CONCLUSIONS: Compared with non-splenectomy, curative treatments combined with splenectomy for patients with HCC and Child B grade liver function showed no different perioperative outcomes but achieved significant survival benefit. Splenectomy is a beneficial factor for patients with HCC and Child B liver function; liver function improved significantly 1 year after splenectomy.