Clinical outcomes of hepatic arterial infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 immunotherapy for unresectable intrahepatic cholangiocarcinoma.

OBJECTIVE: To compare the treatment efficacy and safety of tyrosine kinase inhibitors (TKIs) and anti-programmed cell death 1 (PD-1) immunotherapy combined with transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) for patients with unresectable intrahepatic cholangiocarcinoma (ICC). METHODS: Patients with unresectable ICC received TKIs and anti-PD-1 immunotherapy combined with HAIC (HTP group) or TACE (TTP group) were included. The clinicopathological characteristics, treatment efficacy, and adverse events (AEs) were compared between the two groups. The factors associated with response rate to the treatments were evaluated. RESULTS: A total of 58 patients were enrolled, with 39 in the HTP group and 19 in the TTP group. Patients in the HTP group exhibited a better objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] 48.7% vs 15.8%, P = 0.02; modified RECIST [mRECIST] 61.5% vs 21.1%, P = 0.004) and disease control rate (DCR; 82.1% vs 36.8%, P = 0.001) compared to the TTP group. The median progression-free survival (PFS) rate was not reached and the 1-year PFS rate was 61.9% in the HTP group, whereas the median PFS was 11.0 months and the 1-year PFS rate was 31.6% in the TTP group. The type of treatment and tumor size were significant factors for the response rate. More patients in the HTP group presented rash, abdominal pain and hand-foot syndrome, but all AEs were relieved after symptomatic treatment, and no treatment-related death occurred. CONCLUSIONS: For unresectable ICC, treatment with a combination of HAIC with TKIs and anti-PD-1 immunotherapy was effective and safe. Tumor size might serve as a significant factor for the response rate following treatment for unresectable ICC.

Overexpressed DEPDC1B contributes to the progression of hepatocellular carcinoma by CDK1.

BACKGROUND: Hepatocellular carcinoma (HCC) is the main type of primary liver cancer and shows a heavy burden worldwide. Its recurrence and mortality rate are still uncontrolled by the usage of present treatments. More attention has been focused on exploring specific genes that play important roles in HCC procession, and the function of DEP domain containing 1B (DEPDC1B) in HCC has not been researched. METHODS: Immunohistochemical staining was used to detect the expression level of DEPDC1B in tumor tissues and adjacent normal tissues. After DEPDC1B and CDK1 knockdown in cell lines HEP3B2.1-7 and SK-HEP-1, MTT assay and colony formation assay was used to detect cell growth, flow cytometry assay was used to investigate cell apoptosis and cell cycle, wound-healing assay and Transwell assay were used to examine the tumor cell migration. Moreover, a xenograft model was constructed to research functions of DEPDC1B in tumor growth in vivo. RESULTS: The results show that DEPDC1B knockdown inhibit the progression of HCC, through inhibiting cell proliferation, migration, colony formation, leading to G2 phase arrest, and promoting cell apoptosis in vitro, and CDK1 was selected for further mechanic research according to the results of Human GeneChip prime view. The results of recovery experiment displayed that the functions of DEPDC1B on HCC progression were mediated by CDK1. DEPDC1B knockdown can also inhibit tumor growth in vivo. CONCLUSIONS: The study confirmed that DEPDC1B knockdown restrains the tumor growth in vitro and vivo, and it can interact with CDK1 and rescued by CDK1. The study suggested that DEPDC1B was as a potential therapeutic target involved in HCC growth and progression.

Prognostic alternative splicing regulatory network of RBM25 in hepatocellular carcinoma.

RNA-binding motif protein 25 (RBM25) is a poorly characterized RNA-binding protein that is involved in several biological processes and regulates the proliferation and metastasis of tumor cells. The regulatory role of RBM25 in hepatocellular carcinoma (HCC) is unknown. Here, RBM25 expression and outcomes in HCC patients were evaluated using The Cancer Genome Atlas database. RBM25 was overexpressed in HCC patients compared with the healthy group. The high expression of RBM25 in tumor tissues was significantly related to poor overall survival (P<0.001). Overexpression of RBM25 significantly contributed to poorer survival in male patients and N0 stage patients (P<0.001). Spearman analysis and weighted gene co-expression network analysis identified 694 RBM25-related genes. Protein-protein interaction network analysis revealed the Cluster with the highest score, which positively correlated with RBM25. CDCA5 and INCENP were identified as the core functional genes related to RBM25. The overexpression of CDCA5 and INCENP in HCC patients was examined using the Human Protein Atlas database. The findings collectively indicated that RBM25 may interact with CDCA5 and INCENP to regulate HCC. Our detailed characterization of RBM25 protein interactions and related core functional genes provides a basis for further studies aimed at identifying molecular regulatory pathways or splicing events.

GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis.

The mechanism of cancer metastasis remains poorly understood. Using gene profiling of hepatocellular carcinoma (HCC) tissues, we have identified GOLM1 as a leading gene relating to HCC metastasis. GOLM1 expression is correlated with early recurrence, metastasis, and poor survival of HCC patients. Both gain- and loss-of-function studies determine that GOLM1 acts as a key oncogene by promoting HCC growth and metastasis. It selectively interacts with epidermal growth factor receptor (EGFR) and serves as a specific cargo adaptor to assist EGFR/RTK anchoring on the trans-Golgi network (TGN) and recycling back to the plasma membrane, leading to prolonged activation of the downstream kinases. These findings reveal the functional role of GOLM1, a Golgi-related protein, in EGFR/RTK recycling and metastatic progression of HCC.

Peritumoral Cbl is a strong independent prognostic marker after curative resection of hepatocellular carcinoma.

Growing evidences support the concept that peritumoral microenvironment gene expression is an important element for physicians to make an accurate prognosis. Nonetheless, the correlation between peritumoral ubiquitin ligases and the hepatocellular carcinoma (HCC) survival remains unclear till this present. The expression of intratumoral and peritumoral Casitas B-lineage Lymphoma (Cbl) and epidermal growth factor receptor (EGFR) in hepatocellular carcinomas (HCCs) followed by curative resection was assessed by tissue microarray-based immune-histochemistry in two independent cohorts (n = 352). Their respective prognostic values and other clinicopathologic factors were then evaluated. The peritumoral Cbl density, much higher than that in intratumoral tissue, was an independent prognostic factor for overall survival (P < 0.001) and time to recurrence (P < 0.001) of HCCs after curative resection. The hazard ratio were 1.587 and 1.689, respectively. However, there was no correlation between intratumoral Cbl and prognosis. The peritumoral Cbl was also associated with prognosis even in HCC subgroups with small tumor size, negative AFP, without microvascular invasion and negative HBeAg. After a thorough analysis pertaining to the key role of Cbl on ubiquitination and degradation of activated receptor tyrosine kinases, we eventually discovered the negative correlation between peritumoral Cbl and EGFR (P = 0.015). Furthermore, the combination of peritumoral Cbl and EGFR serves as a much stronger indicator to make an accurate prognosis, especially during early recurrence (P < 0.001). These findings suggest that low expression of peritumoral Cbl and EGFR were positively associated with tumor size, microvascular invasion and patients survival after hepatectomy, highlighting the key role of peritumoral liver milieu in HCC progression.

Involvement of acid-sensing ion channel 1α in hepatic carcinoma cell migration and invasion.

An acidic microenvironment promotes carcinoma cell proliferation and migration. Acid-sensing ion channels (ASICs) are H(+), Ca(2+), and Na(+)-gated cation channels that are activated by changes in the extracellular pH, and ASIC1α may be associated with tumor proliferation and migration. Here, we investigated the role of ASIC1α in hepatocellular carcinoma (HCC) migration and invasion. The expression of ASIC1α was examined in 15 paired HCC and adjacent non-tumor tissues by immunohistochemistry. Reverse transcription (RT)-PCR and Western blotting were used to assess ASIC1α messenger RNA (mRNA) and protein expression in the HCC cell line SMMC-7721 cultured in different pH media or transfected with short hairpin RNA (shRNA) against ASIC1α. Cell migration ability was detected by wound healing and Transwell assays. ASIC1α expression was significantly higher in tumor tissues than in non-tumor tissues, and it was higher in HCC with postoperative metastasis than in that without metastasis. ASIC1α mRNA and protein expression was significantly higher in SMMC-7721 cells cultured at pH 6.5 than in those cultured at pH 7.4 and 6.0. shRNA-mediated silencing of ASIC1α significantly downregulated ASIC1α mRNA and protein expression compared with negative control or untransfected cells and inhibited HCC cell migration and invasion. ASIC1α is overexpressed in HCC tissues and associated with advanced clinical stage. A moderately acidic extracellular environment promoted ASIC1α expression, and silencing of ASIC1α expression inhibited the migration and invasion of HCC cells. Suppression of ASIC1α expression by RNAi attenuated the malignant phenotype of HCC cells, suggesting a novel approach for anticancer gene therapy.

MST4 promotes hepatocellular carcinoma epithelial-mesenchymal transition and metastasis via activation of the p-ERK pathway.

Mammalian sterile-20-like kinase 4 (MST4) has been implicated in cell proliferation and differentiation. In a previous study, we found MST4 to be an important candidate gene for metastatic hepatocellular carcinoma (HCC); however, the molecular mechanism of the promoting role of MST4 in HCC metastasis is poorly understood. In this study, we show that high expression of MST4 was detected in highly invasive HCC cells and in human HCC specimens with vascular invasion. A high level of MST4, associated with large tumor size, microvascular invasion, presence of intrahepatic metastasis, and advanced TNM classification of malignant tumors stage, was an independent prognostic factor for overall survival (P=0.004) and time to recurrence (P=0.001) after hepatectomy. Knockdown of MST4 expression in HCC cells inhibited cell proliferation, colony formation, and invasion, whereas upregulation of MST4 significantly promoted these processes by promoting epithelial-mesenchymal transition (EMT), dependent on the activation of extracellular signal-regulated protein kinase (ERK) signaling pathways. Furthermore, the combination of MST4 and phosphorylated ERK was proven to have more power to predict the outcomes of HCC patients. This study presents clinical evidence for predicting the value of MST4 in HCC overall survival and recurrence and describes the key role of MST4 in facilitating the EMT process via regulating the activation of ERK, indicating its potential role as a target for postoperative adjuvant therapy for HCC.