Urgent need for prognostic markers for hepatocellular carcinoma in the light of genomic instability and non-coding RNA signatures.

Tumor cells induce an immunosuppressive microenvironment which leads towards tumor immune escape. Understanding the intricacy of immunomodulation by tumor cells is essential for immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme which mediates tumor immune escape in various cancers including hepatocellular carcinoma (HCC). IDO up-regulation in HCC may lead to recruitment of regulatory T-cells into tumor microenvironment and therefore inhibit local immune responses and promote metastasis. HCC associated fibroblasts stimulate natural killer cells dysfunction through prostaglandin E2 and subsequently IDO promotes favorable condition for tumor metastasis. IDO up-regulation induces immunosuppression and may enhance the risk of hepatitis C virus and hepatitis B virus induced HCC. Therefore, IDO inhibitors as adjuvant therapeutic agents may have clinical implications in HCC. This review proposes future prospects of IDO not only as a therapeutic target but also as a prognostic marker for HCC.

Dysregulated lipid metabolism has been reported in the progression of hepatocellular carcinoma (HCC). In the present study, we investigated the molecular characteristics of lipid-metabolism-related genes (IMRGs) as prognostic markers for HCC. Multi-dimensional bioinformatics analyses were performed to comprehensively analyze IMRGs, and to construct prognostic prediction signatures. Data of 770 HCC patients and their corresponding 776 IMRGs were downloaded from three databases. Patients were classified into 2 molecular clusters that were associated with overall survival, clinical characteristics, and immune cells. The biological functions of the IMRGs differentially expressed between the 2 clusters were associated with tumor-related metabolic pathways. A 6 IMRG signature (6-IS), consisting of FMO3, SLC11A1, RNF10, KCNH2, ME1, and ZIC2, was established as an independent prognostic factor for HCC. The performance of the signature of 6-IS prognostic was verified in a validation set and compared to an external data set. It was revealed that the 6-IS could effectively predict the prognosis of patients with HCC. This study provides new insights into the role of IMRGs in the pathogenesis of HCC, and presents a novel signature (6-IS) to predict the prognosis of HCC.

Metallothionein (MT)-1 and -2 are low-molecular weight, cysteine-rich, intracellular metal-binding proteins involved in diverse functions, such as metal homeostasis, cell cycle progression, cell differentiation, and carcinogenesis. This study investigated the expression of MT-1 and MT-2 as a prognostic marker in hepatocellular carcinoma (HCC). Expression of MT-1 and MT-2 were evaluated immunohistochemically in tissue microarrays containing samples from 370 HCCs, 336 adjacent noncancerous livers, and 12 normal livers. The relationships between MT-1 and MT-2 expression and the clinicopathological parameters of HCC were assessed. The expression of MT-1 and MT-2 was uniformly strong in the nucleus and cytoplasm of normal liver, but varied in noncancerous livers and HCCs. Loss of nuclear and cytoplasmic expression was significantly more in HCCs than in adjacent noncancerous livers (P < 0.001). The loss of nuclear expression of MT-1 and MT-2 was significantly correlated with high Edmondson-Steiner grade and the presence of microvascular invasion (P < 0.05 each). Multivariate analysis showed that the loss of nuclear expression of MT-1 and MT-2 was an independent poor prognostic factor for both recurrence-free survival and overall survival. The expression of MT-1 and MT-2 may play a role in HCC differentiation and carcinogenesis, and may predict prognosis in patients with HCC.

Poly(C)‑binding protein2 (PCBP2) is a member of the PCBP family, and plays an important role in post‑transcriptional and translational regulation of various signaling molecules through direct binding to single‑stranded poly(C) motifs. PCBP2 has been reported to play a critical role in the development of multiple human tumors. However, whether PCBP2 participates in hepatocellular carcinoma(HCC) development remains largely elusive. Herein, we showed that PCBP2 was upregulated in human HCC tissues and cell lines. Overexpression of PCBP2 predicted significantly worsened prognosis in HCC patients, suggesting that PCBP2 may serve as a prognostic marker of HCC. In addition, we found that depletion of PCBP2 inhibited HCC cell proliferation, accompanying the increase in the cyclin‑dependent kinase inhibitor p27 level. Moreover, we found that high expression of PCBP2 may contribute to sorafenib resistance in HCC cells, involving dysregulated expression of Bax and Bcl‑2 proteins. In conclusion, our results suggest that PCBP2 may serve as a prognostic marker and potential therapeutic target of HCC.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Early diagnosis and treatment of HCC remain a key goal for improving patient survival. Chronic hepatitis B virus (HBV) infection is a major risk factor for HCC development. Pre-S mutants harboring deletions in HBV large surface antigen have been well demonstrated as HBV oncoproteins that dysregulate multiple signaling pathways in hepatocytes, leading to HCC formation. The presence of pre-S mutants in plasma represents important predictive and prognostic markers for HCC in patients with chronic HBV infection. However, the method to detect pre-S mutants remains to be optimized. In this study, we developed a platform, based on the next-generation sequencing (NGS) technology, for detection of pre-S mutants in plasma of HBV-related HCC patients. Compared to the current TA cloning-based analysis, the NGS-based analysis could detect pre-S deletion quantitatively, and the detection rate was significantly more sensitive in 49 plasma analyzed (McNemar’s paired proportion test, P value < 0.0001; simple kappa coefficient, κ = 0.29 (95% CI, 0.12 to 0.46)). Our data suggest that the NGS-based platform may hold a promise for improving the clinical application of pre-S mutants in serving as predictive and prognostic markers for HBV-related HCC.

Background Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second leading reason of cancer-associated deaths around the world.The poor outcome of patients with HCC is attributed to late detection, with more than two-thirds of patients diagnosed at advanced stages of the disease. However, a considerable improvement in survival has been observed (5-year survival up from 40% to 70%) when patients are diagnosed at an early stage and receive potentially curative therapy in the form of liver transplantation, surgical resection, or tumor ablation. Objective Evaluate levels of serum Dickkopf-1, &amp; its significance as a diagnostic &amp; prognostic marker for Hepatocellular Carcinoma. Aim of the work assess the possible diagnostic role of serum DKK1 compared to alpha- fetoprotein which is the slandered marker used for diagnosis of HCC.also DKK1 act as prognostic marker for Hepatocellular Carcinoma. Pateints and Methodes This study had been carried out on 45 subjects diveded into 2 groups,first group include 30 pateints with liver cirrhosis,and second group 15 pateints with HCC.In this group of patients DKK1 was withdrawn before TACE &amp; 3 months post intervention, age range 25-73 year selected from Internal medicine and Hepatology outpatient clinics and inpatient wards at Ain shams university hospitals from March 2019 till January 2020.They were distributed as 25 males and 20 females. There were 13 pateints with child A,17 pateints with child B, &amp; 15 pateints (20%) with child C. Results In this study, the serum levels of serum DKK1 were highest in patients with HCC compared to those with liver cirrhosis. Also DKK1 values significally decreased after intervention(TACE). Conclusion Serum DKK1 act as a diagnostic marker for HCC and its level significally decrease after TACE

MAGI2-AS3/miR-450b-5p/COLEC10 interaction network: A potential therapeutic and prognostic marker in hepatocellular carcinoma.

Objective: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease with a dismal prognosis. However, driver genes and prognostic markers in HCC remain to be identified. It is hoped that in-depth analysis of HCC genomes in relation to available clinicopathological information will give rise to novel molecular prognostic markers.Methods: We collected genomic data of 1,061 HCC patients from previous studies, and performed integrative analysis to identify significantly mutated genes and molecular prognosticators. We employed three MutSig algorithms (MutSigCV, MutSigCL and MutSigFN) to identify significantly mutated genes. The GISTIC2 algorithm was used to delineate focally amplified and deleted genomic regions. Nonnegative matrix factorization (NMF) was utilized to decipher mutational signatures. Kaplan-Meier survival and Cox regression analyses were used to associate gene mutation and copy number alteration with survival outcome. Logistic regression model was applied to test association between gene mutation and mutational signatures.Results: We discovered 11 novel driver genes, including RNF213, VAV3 and TNRC6B, with mutational prevalence ranging from 1% to 3%. Seven mutational signatures were also identified in HCC, some of which were associated with mutations of classical driver genes (e.g., TP53, TERT) as well as alcohol consumption. Focal amplifications of TERT and other druggable targets, including AURKA, were also revealed. Targeting AURKA by a small-molecule inhibitor potently induced apoptosis in HCC cells. We further demonstrated that HCC patients with TERT amplification displayed shortened overall survival independent of other clinicopathological parameters. In conclusion, our study identified novel cancer driver genes and prognostic markers in HCC, reiterating the translational importance of omics data in the precision medicine era.

Centrosome-associated proteins are recognized as prognostic factors in many cancers because centrosomes are critical structures for the cell cycle progression and genomic stability. SAC3D1, however, is associated with centrosome abnormality, although its prognostic potential has not been evaluated in hepatocellular carcinoma (HCC). In this study, 3 independent cohorts (GSE10186, n = 80; TCGA, n = 330 and ICGC, n = 237) were used to assess SAC3D1 as a biomarker, which demonstrated SAC3D1 overexpression in HCC tissues when compared to the matched normal tissues. Kaplan-Meier survival analysis also showed that its overexpression was associated with poor prognosis of HCC with good discriminative ability in 3 independent cohorts (GSE10186, P = 0.00469; TCGA, P = 0.0000413 and ICGC, P = 0.0000114). Analysis of the C-indices and AUC values further supported its discriminative ability. Finally, multivariate analysis confirmed its prognostic significance (GSE10186, P = 0.00695; TCGA, P = 0.0000289 and ICGC, P = 0.0000651). These results suggest a potential of SAC3D1 as a biomarker for HCC.

The development of hepatocellular carcinoma is associated with the chronic inflammation of the liver caused by various factors such as hepatitis B or C virus infection. Previously, we reported DNA binding protein A (dbpA) as a candidate molecule that can accelerate inflammation-induced hepatocarcinogenesis. DbpA belongs to the Y-box binding protein family, and Y-box binding protein-1 (YB-1), the prototype member of this family, is reported to be a prognostic marker of malignant diseases other than hepatocellular carcinoma. The purpose of this study is to examine the significance of the expression of dbpA or of the T-to-G transversion in the dbpA promoter region, which enhances the promoter activity in vitro, for the progression of hepatocellular carcinoma. We studied the expression of dbpA (as well as of YB-1) in 82 formalin-fixed hepatocellular carcinoma tissues by immunohistochemistry and determined the sequence of the dbpA promoter region in 42 frozen hepatocellular carcinoma tissues. We examined the relationship between these findings and the clinicopathologic factors of hepatocellular carcinoma patients. DbpA expression was associated with the advanced stages of hepatocellular carcinoma, and the cases with the nuclear dbpA expression had a poor prognosis. DbpA contributed more significantly to this association than YB-1. Furthermore, the T-to-G transversion in the dbpA promoter region was related to the nuclear localization of dbpA. DbpA was a more significant prognostic marker of hepatocellular carcinoma than YB-1. The T-to-G transversion in the dbpA promoter region was suggested to be a predisposing factor for the progression of hepatocellular carcinoma.

[This corrects the article DOI: 10.3389/fsurg.2022.878648.].

&lt;div&gt;Abstract&lt;p&gt;The long noncoding RNA (lncRNA) &lt;i&gt;MIR22HG&lt;/i&gt; has previously been identified as a prognostic marker in hepatocellular carcinoma. Here, we performed a comprehensive analysis of lncRNA expression profiles from RNA-Seq data and report that &lt;i&gt;MIR22HG&lt;/i&gt; plays a similar role in lung cancer. Analysis of 918 lung cancer and normal lung tissues and lung cancer cell lines revealed that &lt;i&gt;MIR22HG&lt;/i&gt; was significantly downregulated in lung cancer; this decreased expression was associated with poor patient survival. &lt;i&gt;MIR22HG&lt;/i&gt; bound and stabilized the YBX1 protein. Silencing of &lt;i&gt;MIR22HG&lt;/i&gt; triggered both cell survival and cell death signaling through dysregulation of the oncogenes YBX1, MET, and p21. In this &lt;i&gt;MIR22HG&lt;/i&gt; network, p21 played an oncogenic role by promoting cell proliferation and antiapoptosis in lung cancers. &lt;i&gt;MIR22HG&lt;/i&gt; played a tumor-suppressive role as indicated by inhibition of multiple cell cycle–related genes in human primary lung tumors. These data show that &lt;i&gt;MIR22HG&lt;/i&gt; has potential as a new diagnostic and prognostic marker and as a therapeutic target for lung cancer.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Significance:&lt;/b&gt; The lncRNA &lt;i&gt;MIR22HG&lt;/i&gt; functions as a tumor suppressor, with potential use a diagnostic/prognostic marker and therapeutic target in lung cancer. &lt;i&gt;Cancer Res; 78(12); 3207–19. ©2018 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;The long noncoding RNA (lncRNA) &lt;i&gt;MIR22HG&lt;/i&gt; has previously been identified as a prognostic marker in hepatocellular carcinoma. Here, we performed a comprehensive analysis of lncRNA expression profiles from RNA-Seq data and report that &lt;i&gt;MIR22HG&lt;/i&gt; plays a similar role in lung cancer. Analysis of 918 lung cancer and normal lung tissues and lung cancer cell lines revealed that &lt;i&gt;MIR22HG&lt;/i&gt; was significantly downregulated in lung cancer; this decreased expression was associated with poor patient survival. &lt;i&gt;MIR22HG&lt;/i&gt; bound and stabilized the YBX1 protein. Silencing of &lt;i&gt;MIR22HG&lt;/i&gt; triggered both cell survival and cell death signaling through dysregulation of the oncogenes YBX1, MET, and p21. In this &lt;i&gt;MIR22HG&lt;/i&gt; network, p21 played an oncogenic role by promoting cell proliferation and antiapoptosis in lung cancers. &lt;i&gt;MIR22HG&lt;/i&gt; played a tumor-suppressive role as indicated by inhibition of multiple cell cycle–related genes in human primary lung tumors. These data show that &lt;i&gt;MIR22HG&lt;/i&gt; has potential as a new diagnostic and prognostic marker and as a therapeutic target for lung cancer.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Significance:&lt;/b&gt; The lncRNA &lt;i&gt;MIR22HG&lt;/i&gt; functions as a tumor suppressor, with potential use a diagnostic/prognostic marker and therapeutic target in lung cancer. &lt;i&gt;Cancer Res; 78(12); 3207–19. ©2018 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

The long noncoding RNA (lncRNA) MIR22HG has previously been identified as a prognostic marker in hepatocellular carcinoma. Here, we performed a comprehensive analysis of lncRNA expression profiles from RNA-Seq data and report that MIR22HG plays a similar role in lung cancer. Analysis of 918 lung cancer and normal lung tissues and lung cancer cell lines revealed that MIR22HG was significantly downregulated in lung cancer; this decreased expression was associated with poor patient survival. MIR22HG bound and stabilized the YBX1 protein. Silencing of MIR22HG triggered both cell survival and cell death signaling through dysregulation of the oncogenes YBX1, MET, and p21. In this MIR22HG network, p21 played an oncogenic role by promoting cell proliferation and antiapoptosis in lung cancers. MIR22HG played a tumor-suppressive role as indicated by inhibition of multiple cell cycle-related genes in human primary lung tumors. These data show that MIR22HG has potential as a new diagnostic and prognostic marker and as a therapeutic target for lung cancer.Significance: The lncRNA MIR22HG functions as a tumor suppressor, with potential use a diagnostic/prognostic marker and therapeutic target in lung cancer. Cancer Res; 78(12); 3207-19. ©2018 AACR.

Hepatocellular carcinoma (HCC) remains an incurable disease with a very poor clinical outcome. The purpose of this article was to investigate whether the expression or methylation of tetrapeptide repeat domain 36 (TTC36) could be used as a prognostic marker in hepatocellular carcinoma. TCGA database was used to obtain information on HCC gene expression and the associated clinical features of HCC patients. Differentially expressed genes (DEGs) were screened between 374 HCC specimens and 50 nontumor specimens. The expression and prognostic value of TTC36 were analyzed. The correlations between TTC36 and cancer immune infiltrates were investigated via TIMER. In this study, HCC specimens and nontumor specimens were compared and 35 DEGs were found between them. Among the 35 DEGs, the expression of TTC36 was significantly reduced in HCC samples compared with nontumor samples. Survival tests revealed that patients with low TTC36 expression had a shorter overall survival than patients with high TTC36 expression. TTC36 was found to be an independent predictive factor for HCC in both univariate and multivariate regression analyses. TTC36 was negatively regulated by TTC36 methylation, leading to its low expression in HCC tissues. Immune analysis revealed that TTC36 expression has significant correlations with B cell, T cell CD4+, neutrophil, macrophage, and myeloid dendritic cell. Finally, TTC36 expression was dramatically reduced in HCC cells, and overexpression greatly suppressed HCC cell proliferation and invasion, according to our experimental results. Overall, our data suggested that TTC36 could be applied as a prognostic marker for predicting outcome and immune infiltration in HCC.