Novel biomarkers used for early diagnosis and tyrosine kinase inhibitors as targeted therapies in colorectal cancer.

Colorectal cancer (CRC) is the third most common and second most lethal type of cancer worldwide, presenting major health risks as well as economic costs to both people and society. CRC survival chances are significantly higher if the cancer is diagnosed and treated early. With the development of molecular biology, numerous initiatives have been undertaken to identify novel biomarkers for the early diagnosis of CRC. Pathological disorders can be diagnosed at a lower cost with the help of biomarkers, which can be detected in stool, blood, and tissue samples. Several lines of evidence suggest that the gut microbiota could be used as a biomarker for CRC screening and treatment. CRC treatment choices include surgical resection, chemotherapy, immunotherapy, gene therapy, and combination therapies. Targeted therapies are a relatively new and promising modality of treatment that has been shown to increase patients' overall survival (OS) rates and can inhibit cancer cell development. Several small-molecule tyrosine kinase inhibitors (TKIs) are being investigated as potential treatments due to our increasing awareness of CRC's molecular causes and oncogenic signaling. These compounds may inhibit critical enzymes in controlling signaling pathways, which are crucial for CRC cells' development, differentiation, proliferation, and survival. On the other hand, only one of the approximately 42 TKIs that demonstrated anti-tumor effects in pre-clinical studies has been licensed for clinical usage in CRC. A significant knowledge gap exists when bringing these tailored medicines into the clinic. As a result, the emphasis of this review is placed on recently discovered biomarkers for early diagnosis as well as tyrosine kinase inhibitors as possible therapy options for CRC.

Prognosis of Patients With Colorectal Cancer and Apical Lymph Node Metastasis at the Inferior Mesenteric Artery: A Systematic Review and Meta-Analysis.

BACKGROUND: This review was designed to compile the evidence on the prognosis of patients with colorectal cancer and apical lymph node (APN) metastasis and the long-term benefit of inferior mesenteric artery lymph node (IMA-LN) resection. METHODS: We searched the PubMed Central, Cochrane library, EMBASE, and MEDLINE databases from inception until May 2021 for relevant publications. We assess the quality of the studies using the Newcastle Ottawa scale. We conducted a random-effects model meta-analysis and report pooled hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: We analyzed data from 13 studies conducted in Japan, China, and Korea with 6,193 participants. Most studies were retrospective in nature and of low quality. We found that patients with APN metastasis had shorter OSs (pooled HR, 2.41; 95% CI, 1.92-3.02) and PFSs (pooled HR, 2.42; 95% CI, 1.90-3.09) than the patients without the metastasis. We identified significant heterogeneity without publication bias for both outcomes. Moreover, our sensitivity analysis revealed robust estimates were robust for the individual effects. CONCLUSION: Our findings suggest that patients with colorectal cancer and APN metastases have significantly worse OS and DFS than those without the metastasis. However, inclusion of low-quality retrospective studies with high heterogeneity limits the generalizability of study findings.

Safety of laparoscopic resection for colorectal cancer in patients with liver cirrhosis: A retrospective cohort study.

BACKGROUND: Patients with liver cirrhosis represent a high risk group for colorectal surgery. The safety and effectiveness of laparoscopy in colorectal surgery for cirrhotic patients is not clear. The aim of this study was to compare the outcomes of laparoscopic colorectal surgery with those of open procedure for colorectal cancer in patients with liver cirrhosis. MATERIALS AND METHODS: A total of 62 patients with cirrhosis who underwent radical resections for colorectal cancer from 2005 to 2014 were identified retrospectively from a prospective database according to the technique adopted (laparoscopic or open). Short- and long-term outcomes were compared between the two groups. RESULTS: Comparison of laparoscopic group and open group revealed no significant differences at baseline. In the laparoscopic group, the laparoscopic surgery was associated with reduced estimated blood loss (136 vs. 266 ml, p = 0.015), faster first flatus (3 vs. 4 days, p = 0.002) and shorter days to first oral intake (4 vs. 5 days, p = 0.033), but similar operative times (p = 0.856), number of retrieved lymph nodes (p = 0.400) or postoperative hospital stays (p = 0.170). Despite the similar incidence of overall complications between the two groups (50.0% vs. 68.8%, p = 0.133), we observed lower morbidities in laparoscopic group in terms of the rate of Grade II complication (20.0% vs. 50.0%, p = 0.014). Long-term of overall and Disease-free survival rates did not differ between the two groups. CONCLUSION: Laparoscopic colorectal surgery appears to be a safe and less invasive alternative to open surgery in some elective cirrhotic patients in terms of less blood loss or early recovery and does not result in additional harm in terms of the postoperative complications or long-term oncological outcomes.

ELF3 promotes epithelial-mesenchymal transition by protecting ZEB1 from miR-141-3p-mediated silencing in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers and currently the third leading cause of cancer-related deaths, worldwide. Epithelial-mesenchymal transition (EMT) plays a major role in HCC progression. In this study, we first found that the expression of E74-like ETS transcription factor 3 (ELF3), a member of the E-twenty-six family of transcription factors, was increased in HCC tissues, and that ELF3 overexpression was associated with poor prognoses for HCC patients. Gain-of-function and loss-of-function studies revealed that increased ELF3 expression promoted HCC cell proliferation, migration, and invasion, while these processes were inhibited when ELF3 was silenced. Additionally, ELF3 was found to promote EMT, which we demonstrated through decreased E-cadherin expression and increased N-cadherin and fibronectin expression. ELF3 knockdown reversed EMT via repressing ZEB1 expression through miR-141-3p upregulation. Chromatin immunoprecipitation assays revealed that ELF3 bound to the miR-141-3p promoter, suppressing miR-141-3p expression. Taken together, our data show that ELF3 repressed E-cadherin and promoted EMT in HCC cells by suppressing miR-141-3p, thereby activating ZEB1. Thus, ELF3 may be a potential prognostic biomarker and/or therapeutic target for HCC.

Overexpression of Zwint predicts poor prognosis and promotes the proliferation of hepatocellular carcinoma by regulating cell-cycle-related proteins.

INTRODUCTION: Zwint, a centromere-complex component required for the mitotic spindle checkpoint, has been reported to be overexpressed in different human cancers, but it has not been studied in human hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The role of Zwint in hepatocellular carcinoma cell proliferation capacities was evaluated by using cell counting kit-8 (CCK8), flow cytometry, clone formation and tumor formation assay in nude mice. Western blot analysis and qPCR assay were performed to assess Zwint interacting with cell-cycle-related proteins. RESULTS: We report that ZWINT mRNA and protein expression were upregulated in HCC samples and cell lines. An independent set of 106 HCC-tissue pairs and corresponding noncancerous tissues was evaluated for Zwint expression using immunohistochemistry, and elevated Zwint expression in HCC tissues was significantly correlated with clinicopathological features, such as tumor size and number. Kaplan-Meier survival and Cox regression analysis revealed that high expression of Zwint was correlated with poor overall survival and a greater tendency for tumor recurrence. Ectopic expression of Zwint promoted HCC-cell proliferation, and Zwint expression affected the expression of several cell-cycle proteins, including PCNA, cyclin B1, Cdc25C and CDK1. CONCLUSION: Our findings suggest that upregulation of Zwint may contribute to the progression of HCC and may be a prognostic biomarker and potential therapeutic target for treating HCC.

Circular RNA expression is suppressed by androgen receptor (AR)-regulated adenosine deaminase that acts on RNA (ADAR1) in human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy as a result of complex genetic and epigenetic alterations. HCC is characterized by a clear gender disparity for which there is lack of a clear mechanistic understanding. Androgen receptor (AR) is thought to be critical for such bias. Meanwhile, the potential function of circular RNA (circRNA), regulated by RNA editing enzyme, remained largely unknown in malignancy till now. By utilizing circRNA microarray survey coupled with in vitro analysis, we analyzed the influence of AR on circRNA expression in HCC. Our results indicated that AR could suppress circRNA expression by upregulating ADAR1 p110. Such effect is because AR served as a transcriptional activator of ADAR1 promoter. More significantly, data collected from our center strongly suggest that ADAR1 expression can effectively predict HCC patients' prognosis and an abnormal overexpression of ADAR1 is positively correlated with AR in HCC. In addition, we found CircARSP91 (hsa_circ_0085154), one of the circRNAs downregulated by AR in an ADAR1-dependent manner, could inhibit HCC tumor growth both in vitro and in vivo. These findings highlight the fact that AR as a contributing factor for gender disparity in HCC can cause complex consequences though regulation of circRNA expression. Better understanding of the roles of circRNA during HCC initiation and progression will provide a novel angle to develop potential HCC therapies.

Overexpression of NEDD9 promotes cell invasion and metastasis in hepatocellular carcinoma.

Neural precursor cell expressed, developmentally downregulated 9 (NEDD9), is a focal adhesion scaffold protein which has been associated with metastasis in several cancers. Recent study found that NEDD9 expression was upregulated in HCC. However, the precise function of NEDD9 in HCC is still unclear. In the present study, we demonstrated that high NEDD9 expression was associated with the invasiveness of HCC in clinical samples. Moreover, by gain-and-loss function studies, we revealed that silencing of NEDD9 expression inhibited cancer cells proliferation, migration and invasion, while upregulated expression of NEDD9 promoted invasion and metastasis of HCC cells in vitro and in vivo. Further studies revealed that NEDD9 inversely regulated E-cadherin in HCC cells and HCC tissues, which indicated that NEDD9 might promotes the invasion and metastasis of HCC cells through the downregulation of E-cadherin, possibly by inducing EMT. On the whole, our findings thus indicate that NEDD9 may serve as a metastasis-promoting gene and potential therapeutic target for the treatment of hepatocellular carcinoma.

DUSP1 inhibits cell proliferation, metastasis and invasion and angiogenesis in gallbladder cancer.

DUSP1/MKP1 is a dual-specific phosphatase that regulates MAPK activity and is known to play a key role in tumor biology. Its function in gallbladder cancer (GBC) remains largely unknown, however. By exploring its activities in two GBC cell lines (SGC996 and GBC-SD), DUSP1 was found to inhibit GBC cell proliferation, migration and invasion. Moreover, DUSP1 inhibited GBC growth and metastasis in nude mice subcutaneously xenografted with SGC996 cells. The tumor suppression appeared to be mediated via the DUSP1-pERK/MAPK-MMP2 signal pathway. Angiogenesis was associated with the tumor metastasis in the mouse model and was impaired by DUSP1, which suppressed VEGF expression. These results suggest that DUSP1 suppresses GBC growth and metastasis by targeting the DUSP1-pERK-MMP2/VEGF axis. Identification of the DUSP1-pERK-MMP2/VEGF signals may provide new biomarkers and/or therapeutic targets to better suppress GBC metastasis in the future.

Downregulated expression of DIXDC1 in hepatocellular carcinoma and its correlation with prognosis.

Dishevelled-Axin domain containing 1 (DIXDC1) is a DIX (Dishevelled-Axin) domain possessing protein that acts as a positive regulator of the Wnt pathway. Although DIXDC1 has been investigated in several cancers, it has not yet been studied in human hepatocellular carcinoma (HCC). The purpose of the current study was to investigate the expression pattern of DIXDC1 and assess the clinical significance of DIXDC1 expression in HCC patients. Data containing three independent investigations from Oncomine database demonstrated that DIXDC1 mRNA was downregulated in HCC compared with matched non-cancerous tissues. Similar results were also obtained in 25 paired HCC tissues and corresponding non-cancerous tissues by qPCR and Western blot analysis. Additionally, another independent set of 140 pairs of HCC specimens was evaluated for DIXDC1 expression by IHC and demonstrated that reduced expression of DIXDC1 in 50.7 % (71/140) of HCC tissues was significantly correlated with tumor size (p = 0.024), tumor differentiation (p < 0.001), tumor thrombi (p = 0.019), TNM stage (p = 0.019), and BCLC stage (p = 0.008). Importantly, Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC patients and found that DIXDC1 protein expression was one of the independent prognostic factors for overall survival of HCC patients.

NEK2 regulates stem-like properties and predicts poor prognosis in hepatocellular carcinoma.

NEK2 has been estimated to play an important role in cancer progression. However, its relevance in hepatocellular carcinoma (HCC) has not yet been explored. Immunohistochemistry revealed NEK2 expression was upregulated in HCC. NEK2-positive hepatocellular carcinoma patients were associated with poor prognosis after surgery compared with NEK2-negative patients based on Kaplan-Meier curves. Deletion of NEK2 reduced self-renewal properties and chemotherapeutic resistance, and decreased the stemness associated genes in cell lines. NEK2 was associated with unfavorable outcomes in HCC patients, and was revealed to regulate self-renewal property by means of Wnt/ß-catenin signaling, and chemotherapeutic resistance by preferential regulation of the expression of ABCG2 and ALDH1A1 in HCC cells.

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma.

Sorafenib, an orally-available kinase inhibitor, is the only standard clinical treatment against advanced hepatocellular carcinoma. However, development of resistance to sorafenib has raised concern in recent years due to the high-level heterogeneity of individual response to sorafenib treatment. The resistance mechanism underlying the impaired sensitivity to sorafenib is still elusive though some researchers have made great efforts. Here, we provide a systemic insight into the potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma depending on abundant previous studies and reports.

[Minimally invasive surgery for colorectal cancer with liver metastasis].

OBJECTIVE: To investigate the minimal invasive surgery for simultaneously treating synchronous colorectal cancer with liver metastasis. METHODS: From the clinical data of our department between March 2006 to June 2008, retrospectively reviewed and analyzed 5 typical cases of synchronous colorectal cancer with liver metastasis. All were treated with 5 different strategies of minimal invasive surgery. RESULTS: All underwent laparoscopic colorectal surgery, i.e. open hepatectomy, laparoscopic-assisted hepatectomy, laparoscopic hepatectomy, laparoscopic hepatectomy plus radiofrequency ablation and multiple therapy respectively. The mean operative time was 177 minutes, the mean blood loss 126 ml, the time of gastrointestinal function recovery 48-72 hours and the mean hospital stay 7 days. In the follow-up of 10-27 months for all 5 patients, one suffered hepatic recurrence and one died. CONCLUSION: Simultaneous minimal invasive surgery is an optional and ideal method for treating synchronous colorectal cancer with liver metastasis.