Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. A great effort in developing selective drugs to target components of the β-catenin pathway with anticancer activity is underway but only a few of them have reached phase I clinical trials. We aim to review the role of β-catenin pathway on hepatocarcinogenesis and liver cancer stem cell maintenance. We also evaluated the use of small molecules targeting the Wnt/β-catenin pathway with potential application for treatment of HCC.

/pdf/targeting-wnt-b-catenin-pathway-in-hepatocellular-carcinoma-526r2hi02l.pdf

Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment.

The development of combination immunotherapy based on the mediation of regulatory mechanisms of the tumor immune microenvironment (TIME) is promising. However, a deep understanding of tumor immunology must involve the systemic tumor immune environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial transcriptomics for the studies of STIE, TIME, and their interactions, which may reveal heterogeneity in immunotherapy responses as well as the dynamic changes essential for the treatment effect. We review the evidence from preclinical and clinical studies related to TIME, STIE, and their significance on overall survival, through different immunomodulatory pathways, such as metabolic and neuro-immunological pathways. We also evaluate the significance of the STIE, TIME, and their interactions as well as changes after local radiotherapy and systemic immunotherapy or combined immunotherapy. We focus our review on the evidence of lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, aiming to reshape STIE and TIME to enhance immunotherapy efficacy. 

/pdf/reshaping-the-systemic-tumor-immune-environment-stie-and-3moc9cvg.pdf

Reshaping the systemic tumor immune environment (STIE) and tumor immune microenvironment (TIME) to enhance immunotherapy efficacy in solid tumors

Motivation A key goal of computational personalized medicine is to systematically utilize genomic and other molecular features of samples to predict drug responses for a previously unseen sample. Such predictions are valuable for developing hypotheses for selecting therapies tailored for individual patients. This is especially valuable in oncology, where molecular and genetic heterogeneity of the cells has a major impact on the response. However, the prediction task is extremely challenging, raising the need for methods that can effectively model and predict drug responses. Results In this study, we propose a novel formulation of multi-task matrix factorization that allows selective data integration for predicting drug responses. To solve the modeling task, we extend the state-of-the-art kernelized Bayesian matrix factorization (KBMF) method with component-wise multiple kernel learning. In addition, our approach exploits the known pathway information in a novel and biologically meaningful fashion to learn the drug response associations. Our method quantitatively outperforms the state of the art on predicting drug responses in two publicly available cancer datasets as well as on a synthetic dataset. In addition, we validated our model predictions with lab experiments using an in-house cancer cell line panel. We finally show the practical applicability of the proposed method by utilizing prior knowledge to infer pathway-drug response associations, opening up the opportunity for elucidating drug action mechanisms. We demonstrate that pathway-response associations can be learned by the proposed model for the well-known EGFR and MEK inhibitors. Availability and implementation The source code implementing the method is available at http://research.cs.aalto.fi/pml/software/cwkbmf/ Contacts muhammad.ammad-ud-din@aalto.fi or samuel.kaski@aalto.fi Supplementary information Supplementary data are available at Bioinformatics online.

pdf/drug-response-prediction-by-inferring-pathway-response-5ay633kj2f.pdf

Drug response prediction by inferring pathway-response associations with kernelized Bayesian matrix factorization

Rationale: Metastasis, the development of secondary malignant growth at a distance from a primary tumor, is the main cause of cancer-associated death. However, little is known about how metastatic cancer cells adapt to and colonize in the new organ environment. Here we sought to investigate the functional mechanism of cholesterol metabolic aberration in colorectal carcinoma (CRC) liver metastasis. Methods: The expression of cholesterol metabolism-related genes in primary colorectal tumors (PT) and paired liver metastases (LM) were examined by RT-PCR. The role of SREBP2-dependent cholesterol biosynthesis pathway in cell growth and CRC liver metastasis were determined by SREBP2 silencing in CRC cell lines and experimental metastasis models including, intra-splenic injection models and liver orthotropic injection model. Growth factors treatment and co-culture experiment were performed to reveal the mechanism underlying the up-regulation of SREBP2 in CRC liver metastases. The in vivo efficacy of inhibition of cholesterol biosynthesis pathway by betulin or simvastatin were evaluated in experimental metastasis models. Results: In the present study, we identify a colorectal cancer (CRC) liver metastasis-specific cholesterol metabolic pathway involving the activation of SREBP2-dependent cholesterol biosynthesis, which is required for the colonization and growth of metastatic CRC cells in the liver. Inhibiting this cholesterol biosynthesis pathway suppresses CRC liver metastasis. Mechanically, hepatocyte growth factor (HGF) from liver environment activates SREBP2-dependent cholesterol biosynthesis pathway by activating c-Met/PI3K/AKT/mTOR axis in CRC cells. Conclusion: Our findings support the notion that CRC liver metastases show a specific cholesterol metabolic aberration. Targeting this cholesterol biosynthesis pathway could be a promising treatment for CRC liver metastasis.

Organ-specific cholesterol metabolic aberration fuels liver metastasis of colorectal cancer.

Background In the present study, we aim to investigate the potential role of propofol in the tumor progression of colon cancer. Methods Human colon cancer cell lines were cultured and exposed with 8 μg/mL propofol. RNA interference was performed to silence the expression of HOTAIR or STAT3 to explore their biological functions in colon cancer. Cell apoptosis and invasion were assessed using flow cytometry and transwell assays, respectively. Quantitative real-time PCR, western blot, and immunohistochemistry were subjected to measure the expression patterns of HOTAIR, STAT3, Wnt signaling factors, and epithelial-mesenchymal transition-related markers, respectively. Besides, nude mice were transplanted with colon cancer cells for further exploration. Tumor formation, volume, and weight were evaluated to validate the in vitro findings. Results Propofol treatment promoted cell apoptosis and inhibited cell invasion in colon cancer cells, while the effects were reversed by HOTAIR overexpression. Additionally, STAT3 positively regulated HOTAIR expression, which was also negatively modulated by propofol. Moreover, STAT3 and HOTAIR were shown to independently regulate colon cancer cell apoptosis and invasion. Furthermore, HOTAIR could stimulate Wnt signaling pathway via inhibiting WIF-1 expression and upregulating β-catenin expression, which was also demonstrated by in vivo study. Conclusion Taken together, the current study demonstrated that propofol exerts the inhibition on cell invasion and promotion on cell apoptosis through regulating STAT3/HOTAIR by activating WIF-1 and suppressing Wnt pathway, indicating that propofol might serve as a therapeutic role for colon cancer patients in the future.

Effects of propofol on colon cancer metastasis through STAT3/HOTAIR axis by activating WIF‐1 and suppressing Wnt pathway

Background Protein phosphatase magnesium-dependent 1δ (PPM1D) is an oncogene, overexpressed in many solid tumors, including ovarian cancer and breast cancer. The current study examined the expression and the prognostic value of PPM1D mRNA in human hepatocellular carcinoma (HCC). Methods Total RNA was extracted from 86 HCC and paired non-cancerous liver tissues. PPM1D mRNA expression was determined by real-time quantitative reverse transcriptase-polymerase chain reaction (qPCR). Immunohistochemistry assay was used to verify the expression of ppm1d protein in the HCC and non-cancerous liver tissues. HCC patients were grouped according to PPM1D mRNA expression with the average PPM1D mRNA level in non-cancerous liver tissue samples as the cut-off. Correlations between clinicopathologic variables, overall survival and PPM1D mRNA expression were analyzed. Findings PPM1D mRNA was significantly higher in HCC than in the paired non-cancerous tissue (p<0.01). This was confirmed by ppm1d staining. 56 patients were classified as high expression group and the other 30 patients were categorized as low expression group. There were significant differences between the two groups in term of alpha-fetoprotein (α-FP) level (p<0.01), tumor size (p<0.01), TNM stage (p<0.01), recurrence incidence (p<0.01) and family history of liver cancer (p<0.01). The current study failed to find significant differences between the two groups in the following clinical characteristics: age, gender, portal vein invasion, lymphnode metastasis, hepatitis B virus (HBV) infection and alcohol intake. Survival time of high expression group was significantly shorter than that of low expression group (median survival, 13 months and 32 months, respectively, p<0.01). Conclusion Up-regulation of PPM1D mRNA was associated with progressive pathological feature and poor prognosis in HCC patients. PPM1D mRNA may serve as a prognostic marker in HCC.

/pdf/protein-phosphatase-magnesium-dependent-1d-ppm1d-mrna-2q2pr95x9q.pdf

Protein Phosphatase Magnesium-Dependent 1δ (PPM1D) mRNA Expression Is a Prognosis Marker for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a primary cancer of the liver. Target therapy may improve prognosis of HCC. In the present study, we evaluated the inhibition of the Wnt/β-catenin pathway as a potential therapeutic approach. HepG2 cells were treated with the β-catenin inhibitor FH535. β-catenin protein expression was semi-quantitatively assessed using western blot analysis. Cell proliferation was examined with a 3‑(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay. The mRNA expression of nitric oxide synthase (iNOS) was detected by reverse transcription polymerase chain reaction. The Griess assay was used to determine nitric oxide (NO) concentration. FH535 inhibited the proliferation of HepG2 cells and decreased β-catenin protein expression. mRNA expression of iNOS, a target gene of the Wnt/β-catenin pathway, was decreased in FH535‑treated HepG2 cells compared to the control group. NO production was also reduced by FH535. In conclusion, the β-catenin inhibitor FH535 may inhibit HCC cell proliferation via downregulation of the Wnt/β-catenin pathway. Thus, targeting this pathway may be useful in HCC therapy.

https://www.spandidos-publications.com/10.3892/mmr.2014.1928/download

FH535 inhibits the proliferation of HepG2 cells via downregulation of the Wnt/β‑catenin signaling pathway

Hepatocellular carcinoma (HCC) is the most common primary liver cancer in the world. Although great advances in HCC diagnosis and treatment have been achieved, due to the complicated mechanisms in tumor development and progression, the prognosis of HCC is still dismal. Recent studies have revealed that the Warburg effect is related to the development, progression and treatment of various cancers; however, there have been a few explorations of the relationship between glycolysis and HCC prognosis.mRNA expression profiling was downloaded from public databases. Gene set enrichment analysis (GSEA) was used to explore glycolysis-related genes (GRGs), and the LASSO method and Cox regression analysis were used to identify GRGs related to HCC prognosis and to construct predictive models associated with overall survival (OS) and disease-free survival (DFS). The relationship between the predictive model and the tumor mutation burden (TMB) and tumor immune microenvironment (TIME) was explored. Finally, real-time PCR was used to validate the expression levels of the GRGs in clinical samples and different cell lines.Five GRGs (ABCB6, ANKZF1, B3GAT3, KIF20A and STC2) were identified and used to construct gene signatures to predict HCC OS and DFS. Using the median value, HCC patients were divided into low- and high-risk groups. Patients in the high-risk group had worse OS/DFS than those in the low-risk group, were related to higher TMB and were associated with a higher rate of CD4+ memory T cells resting and CD4+ memory T cells activated. Finally, real-time PCR suggested that the five GRGs were all dysregulated in HCC samples compared to adjacent normal samples.We identified five GRGs associated with HCC prognosis and constructed two GRGs-related gene signatures to predict HCC OS and DFS. The findings in this study may contribute to the prediction of prognosis and promote HCC treatment. 

/pdf/identification-of-a-glycolysis-related-gene-signature-for-tkwk24kf.pdf

Identification of a glycolysis-related gene signature for predicting prognosis in patients with hepatocellular carcinoma

Possible benefit of splenectomy in liver transplantation for autoimmune hepatitis

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant gastrointestinal tumor with a poor prognosis. Serum biomarker carbohydrate antigen 19-9 (CA19-9) was the only well-established biomarker for PDAC with inadequate efficacy. This present study aimed to determine the ability of PIVKA-II to discriminate PDAC from pancreatic benign lesions and predict vascular invasion preoperatively. Methods: Patients who underwent pancreatic surgery from 2017 to 2020 were enrolled. We examined the differential diagnostic ability of protein induced by vitamin K absence II (PIVKA-II), CA19-9, and their combination and 138 with PDAC evaluated the predictive value of PIVKA-II for vascular invasion in PDAC. Methods: A total of 138 patients with PDAC and 90 patients with pancreatic benign lesions who underwent pancreatic surgery from 2017 to 2020 were enrolled. The clinicopathological characteristics were recorded. Results: There was a significant difference in levels of serum PIVKA-II between PDAC patients and patients with pancreatic benign lesions (p < 0.001). When the cut-off value was set to 28.9 mAU/mL according to the ROCs, the AUC, sensitivity, and specificity of PIVKA-II were 0.787, 68.1%, and 83.3%, respectively. The combined PIVKA-II and carbohydrate antigen 19-9 (CA19-9) enhanced the diagnostic accuracy, and the AUC, sensitivity, and specificity were 0.945, 87.7%, and 94.4%, respectively. PIVKA-II > 36.4 mAU/mL were independent predictive factors of vascular invasion in PDAC (p < 0.001). Conclusion: PIVKA-II was a potential diagnostic biomarker to differentiate PDAC from pancreatic benign lesions. PIVKA-II was complementary to CA19-9, and the combination enhanced the differential diagnostic performance. PIVKA-II > 36.4 mAU/mL was an independent predictive factor of vascular invasion in PDAC.

/pdf/protein-induced-by-vitamin-k-absence-ii-a-potential-3ojolqib.pdf

Protein Induced by Vitamin K Absence II: A Potential Biomarker to Differentiate Pancreatic Ductal Adenocarcinoma from Pancreatic Benign Lesions and Predict Vascular Invasion

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