Impact of primary tumor resection on the survival of patients with unresectable colon cancer liver metastasis at different colonic subsites: a propensity score matching analysis.

OBJECTIVE: To investigate the effect of primary tumor resection (PTR) on the prognosis of patients with unresectable colon cancer liver metastasis (UCCLM) at seven colonic subsites using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Propensity score matching (PSM) was performed to balance selection bias using all available variables that could be of potential relevance. After matching, the groups were redefined in a 1:1 ratio using the nearest method. Cancer-specific survival (CSS) was compared among the patients of PTR and non-PTR groups. Cox regression models were used to identify the prognostic factors for CSS. RESULTS: CSS was significantly different between all groups. Cox regression analysis showed that PTR was an independent prognostic factor for all groups. After PSM, PTR significantly prolonged CSS for all groups. Subgroup analysis showed that PTR did not improve the prognosis of N2 stage patients in the cecum, ascending colon, and descending colon groups; T1 + T2 stage patients in the hepatic flexure group; and patients with a tumor size ≤5 cm in the splenic flexure group. Segmental colectomy could prolong CSS of patients in the cecum, ascending colon, transverse colon, splenic flexure, and sigmoid colon groups, while extended colectomy could prolong CSS of patients in the hepatic flexure and descending colon groups. CONCLUSION: At different colonic subsites, UCCLM patients had different CSS. PTR could improve their prognosis, however, N stage, T stage, and tumor size are important reference indicators. In addition to patients in the hepatic flexure and descending colon groups, we suggested that patients in other groups should choose segmental colectomy.

The expression profiles and prognostic values of HSP70s in hepatocellular carcinoma.

BACKGROUND: The HSP70 family of heat shock protein plays a critical role in protein synthesis and transport to maintain protein homeostasis. Several studies have indicated that HSP70s are related to the development and occurrence of various cancers. METHODS: The relationship between the overall survival rate of hepatocellular carcinoma patients and the expression of 14 HSP70s from multiple databases, such as TCGA, ONCOMINE, cBioPortal was investigated. Western Blot and PCR were used to evaluate HSPA4 and HSPA14 expressions in various HCC cells to identify suitable cell lines for further experiments .Wound-healing assays, Transwell assays and EdU assays were used to verify the effects of HSPA4 and HSPA14 on the function of hepatocellular carcinoma cells, and statistical analysis was performed. RESULTS: Hepatocellular carcinoma tissues significantly expressed the 14 HSP70s compared to the normal samples. Besides, the high HSPA1A, HSPA1B, HSPA4, HSPA5, HSPA8, HSPA13, and HSPA14 expressions were inversely associated with the overall survival rate of patients, tumor grade, and cancer stage. A PPI regulatory network was constructed using the 14 HSP70s proteins with HSPA5 and HSPA8 at the network center. Univariate and multivariate analyses showed that HSPA4 and HSPA14 could be independent risk factors for the prognosis of hepatocellular carcinoma patients. Cell experiments have also confirmed that reducing HSPA4 and HSPA14 expressions can inhibit the invasion, metastasis, and proliferation of hepatocellular carcinoma cells. CONCLUSIONS: Therefore, the HSP70s significantly influence the occurrence and development of hepatocellular carcinoma. For instance, HSPA4 and HSPA14 can be novel therapeutic targets and prognostic biomarkers for hepatocellular carcinoma.

Primary tumor resection improves prognosis of unresectable carcinomas of the transverse colon including flexures with liver metastasis: a preliminary population-based analysis.

PURPOSE: Studies on unresectable colorectal cancer liver metastasis(CRLM) rarely analyze the prognosis of the patients from the point of colonic subsites. We aimed to evaluate the effect of primary tumor resection (PTR) and different scope of colectomy on the prognosis of patients with unresectable transverse colon cancer liver metastasis (UTCLM), hepatic flexure cancer liver metastasis (UHFLM), and splenic flexure cancer liver metastasis (USFLM). PATIENTS AND METHODS: The patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. Cox proportional hazards regression models were used to identify prognostic factors of overall survival (OS) and cause-specific survival (CSS). Kaplan-Meier analyses and log-rank tests were conducted to assess the effectiveness of PTR on survival. RESULTS: In total, this study included a cohort of 1960 patients: 556 cases of UHFLM, 1008 cases of UTCLM, and 396 cases of USFLM. The median survival time of whole patients was 11.0 months, ranging from 7.0 months for UHFLM patients to 15.0 months for USFLM patients. USFLM patients had the best OS and CSS, followed by UTCLM patients. UHFLM patients had the worst OS and CSS (All P < 0.001). PTR could improve the OS and CSS of UTCLM, UHFLM, and USFLM (All P < 0.001). Subgroups analysis revealed that USFLM patients with tumor size≤5 cm and negative CEA had not demonstrated an improved OS and CSS after PTR. Multivariate analysis showed that PTR and perioperative chemotherapy were common independent prognostic factors for UHFLM, UTCLM, and USFLM patients. There was no difference between segmental colon resection and larger colon resection on CSS of UHFLM, UTCLM, and USFLM patients. CONCLUSIONS: We confirmed the different survival of patients with UTCLM, UHFLM, and USFLM, and for the first time, we proved that PTR could provide survival benefits for patients with unresectable CRLM from the perspective of colonic subsites of transverse colon, hepatic flexure, and splenic flexure. Besides, PTR may not improve the prognosis of USFLM patients with CEA- negative or tumor size≤5 cm. For oncologic outcomes, we concluded that segmental colon resection seemed an effective surgical procedure for UTCLM, UHFLM, and USFLM.

TAB3 upregulates PIM1 expression by directly activating the TAK1-STAT3 complex to promote colorectal cancer growth.

Transforming growth factor-ß-activated kinase 1 (TAK1)-binding protein 3 (TAB3) and the proviral integration site for Moloney murine leukaemia virus 1 (PIM1) are implicated in cancer development. In this study, we investigated the relationship between TAB3 and PIM1 in colorectal cancer (CRC) and determined the potential role and molecular mechanism of TAB3 in PIM1-mediated CRC growth. We found that TAB3 and PIM1 expression levels were positively correlated in CRC tissues. The knockdown of TAB3 significantly decreased PIM1 expression and inhibited CRC proliferation in vitro and in vivo. The upregulation of PIM1 rescued the decreased cell proliferation induced by TAB3 knockdown, whereas PIM1 knockdown decreased TAB3-enhanced CRC proliferation. Additionally, TAB3 regulates PIM1 expression through the STAT3 signalling pathway and confirmed a positive correlation between TAB3 and phosphorylated-STAT3 expression in CRC tissues. Patients with high expression of TAB3 and phosphorylated-STAT3 had the worst prognosis. Mechanistically, TAB3 regulates PIM1 expression by promoting STAT3 phosphorylation and activation through the formation of the TAB3-TAK1-STAT3 complex. Overall, a novel CRC regulatory circuit involving the TAB3-TAK1-STAT3 complex and PIM1 was identified, the dysfunction of which may contribute to CRC tumorigenesis.

Modified median hepatic fissure approach for resection of liver tumours located in the angle between the root of the middle and right hepatic veins.

BACKGROUND: Liver tumours between the root angle of the middle and right hepatic veins are a special type of liver segment VIII tumour. In this study, we designed a modified median hepatic fissure approach to remove these tumours. The safety and effectiveness of the approach were evaluated. MATERIALS AND METHODS: From April 2015 to November 2019, 11 patients with liver tumours between the angle of the middle and right hepatic veins underwent this modified median hepatic fissure approach. We retrospectively analysed data from the perioperative periods of these 11 patients, including general condition, operation time, intraoperative bleeding, and postoperative complications. Disease-free survival and overall survival were assessed. RESULTS: Of the 11 patients, 9 patients had primary hepatocellular carcinoma and 2 had colorectal liver metastases. The average intraoperative blood loss was 285 mL (150-450 mL). Two patients developed postoperative bile leakage, but there were no significant serious complications, such as intraabdominal bleeding and liver failure, in any of the patients. The liver function returned to the normal range on the 5th day after surgery. Of the 11 patients, 5 have survived for more than 3 years (45.5%), and 4 have been disease-free for more than 3 years (36.3%). CONCLUSIONS: For liver tumours between the root angle of the middle and right hepatic veins, the modified median hepatic fissure approach is a safe and feasible method.

Efficacy and safety of Seprafilm for preventing intestinal obstruction after gastrointestinal neoplasms surgery: a systematic review and meta-analysis.

OBJECTIVE: It was controversial that hyaluronate-carboxy-methylcellulose-based membrane (Seprafilm) could prevent intestinal obstruction after gastrointestinal neoplasms operation. This study aimed to evaluate the efficacy and safety of Seprafilm in preventing postoperative intestinal obstruction of gastrointestinal neoplasms patients. METHODS: A systematic research of multiple databases was performed to identify relevant studies, and the studies satisfying the inclusion criteria were included. Risk ratio (RR), weighted mean difference (WMD), and 95% confidence intervals were calculated using RevMan 5.3. RESULTS: 2937 patients from 10 studies who were enrolled in this meta-analysis were divided into the Seprafilm group (n = 1334) and the control group (n = 1603). The Seprafilm group had lower incidence of intestinal obstruction (RR, 0.52; 95% CI, 0.38-0.70; p < .0001), reoperation rates due to intestinal obstruction (RR, 0.48; 95% CI, 0.28 - 0.80; p = .005), incidence of overall complications (RR, 0.77; 95% CI, 0.61-0.97; p = .03) and higher serum creatinine on postoperative day 5 (WMD, 0.15; 95% CI, 0.05-0.25; p = .003). There were no differences regarding time to intestinal obstruction after operation, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, white blood cell count results on day 5 and 7, serum creatinine on day 7, hospital stay, and incidence of intra-abdominal infection, wound infection, anastomotic leakage between the 2 groups. CONCLUSIONS: This meta-analysis provided valuable evidence-based support for the efficacy and safety of Seprafilm in preventing postoperative intestinal obstruction of gastrointestinal neoplasms patients. However, more multicenter randomized controlled trials from different countries are needed.

Human Leukocyte Antigen F Locus Adjacent Transcript 10 Overexpression Disturbs WISP1 Protein and mRNA Expression to Promote Hepatocellular Carcinoma Progression.

Recently, studies on transcriptome-proteome relationships have revealed mRNA/protein expression discordance for certain genes and speculated that protein posttranslational modification (PTM) may be involved. However, there is currently no evidence to support this hypothesis. Wnt-induced secreted protein-1 (WISP1) is the downstream target gene of ß-catenin and plays an important role in tumorigenesis and progression, but the expression and role of WISP1 in different tumor types are controversial. Here, we first confirmed that WISP1 protein expression was significantly down-regulated in hepatocellular carcinoma (HCC) tissue and could be an independent predictor of poor prognosis for patients with HCC. In vivo and in vitro evidence was provided that WISP1 can suppress HCC cell proliferation. Further studies have found that low WISP1 protein expression was related to expression of human leukocyte antigen F locus adjacent transcript 10 (FAT10), a specific ubiquitin-like protein with both degradation and stabilization functions, which plays an important role in PTM. FAT10 overexpression facilitated WISP1 degradation by FAT10ylation to decrease WISP1 protein expression, thus promoting HCC proliferation. Interestingly, we found and demonstrated that FAT10 overexpression could result in WISP1 protein/mRNA expression discordance, with protein expression decreasing while mRNA expression increased. The underlying mechanism is that FAT10 exerts substrate stabilization and degradation functions simultaneously, while FAT10 overexpression promotes WISP1 mRNA expression by stabilizing ß-catenin and directly degrades WISP1 protein. Conclusion: Our study demonstrated that overexpression of FAT10 results in expression discordance between WISP1 protein and mRNA, thereby promoting HCC progression by down-regulating WISP1 protein expression.

Non-functional pancreatic neuroendocrine tumours: emerging trends in incidence and mortality.

BACKGROUND: Our aim was to determine the epidemiology and recent changes in the trends of non-functional pancreatic neuroendocrine tumours (NF-pNETs) at the population level. In addition, we explored the risk factors that are associated with survival duration. METHODS: Cases were identified form the Surveillance, Epidemiology, and End Results (SEER) Programme database from 2000 to 2014. Data on incidence and incidence-based (IB) mortality for NF-pNET were obtained from this database. Secular trends in age-adjusted incidence and IB mortality were determined by using the Joinpoint Regression program. Data analyses were performed using chi-square tests, Kaplan-Meier curves and Cox proportional hazards regression. RESULTS: Overall, 4766 patients diagnosed with NF-pNET with a median age of 59 years were identified through our descriptive criteria. Caucasian patients accounted for the majority of the study population, and the proportion of patients with distant disease significantly decreased during our study period. Overall, there was an increase in incidence and IB mortality for NF-pNET; however, the rate of increase decreased during the recent years. In addition, the incidence trends of NF-pNET located in the pancreatic head significantly increased, and rates fo increase in IB mortality for NF-pNET in the pancreatic tail decreased in recent years. Additionally, the 1-, 5-, and 10-year survival rates were 79.0, 51.8, 38.1%, respectively. Furthermore, patient age, tumour grade, stage at diagnosis, tumour size, tumour site and resection were associated with mortality. CONCLUSION: Despite increases in incidence and IB mortality, the rate of change in IB mortality for NF-pNET has decreased in recent years. Survival duration displayed a secular increase during the overall period, and the prognosis and survival duration of patients were closely related to the time of diagnosis, age of the patients and size and location of the tumour. Appropriate treatment adjustments based on tumour stage may thus facilitate improvements in patient outcomes.

Intrahepatic bile duct exploration lithotomy is a useful adjunctive hepatectomy method for bilateral primary hepatolithiasis: an eight-year experience at a single centre.

BACKGROUND: To evaluate the perioperative and long-term results of intrahepatic bile duct exploration lithotomy (IHBDIL) combined with hepatectomy for patients with complicated bilateral primary hepatolithiasis. METHODS: A study was conducted involving 56 patients with complicated bilateral primary hepatolithiasis who underwent IHBDIL combined with hepatectomy at our hospital from January 2006 to December 2014. The perioperative and long-term outcomes that were retrospectively analysed included the stone clearance rate, operative morbidity and mortality, and stone recurrence rate. Patients with a preoperative diagnosis of cholangiocarcinoma were excluded. RESULTS: In all 56 patients, hepatic duct stones were located in the bilateral IHBD. The surgical method was IHBDIL combined with hepatectomy. Postoperative complications occurred in 15 patients (26.8%), 14 patients responded to conservative management, and there was 1 case of postoperative mortality because of hepatic failure. The overall initial success rate of stone clearance was 85.7%, and the final clearance rate was 92.9% following postoperative choledochoscopic lithotripsy. The stone recurrence rate was 13.5%, and the occurrence of postoperative cholangitis was 10.9% during the follow-up period. CONCLUSION: IHBDIL combined with hepatectomy is a safe, effective, and promising treatment for patients with complicated bilateral primary hepatolithiasis. The perioperative and long-term outcomes are satisfactory for complicated bilateral primary hepatolithiasis.

Learning curve for performing choledochotomy bile duct exploration with primary closure after laparoscopic cholecystectomy.

BACKGROUND: Primary closure after laparoscopic cholecystectomy (LC) and laparoscopic common bile duct exploration (LCBDE) is a safe and effective approach for treating cholecystolithiasis with choledocholithiasis. The aim of this study was to evaluate the learning curve of performing primary closure after LC+LCBDE. METHODS: We retrospectively identified all patients who underwent primary closure after LC+LCBDE performed by a single surgeon from January 2009 to April 2015 in our institution, and analyzed preoperative, intraoperative, and postoperative data using the cumulative sum (CUSUM) analysis to evaluate the learning curve for this procedure. RESULTS: Overall, there were 390 patients. The total postoperative complications rate was 7.2%, including bile leakage in 9 (2.3%) patients and retained common bile duct stone in 3 (0.8%) patients. The CUSUM operating time (OT) learning curve was best modeled by the equation: CUSUMOT = 312.209 × procedure0.599 × e(-0.011×procedure) + 122.608 (R2 = 0.96). The learning curve was composed of two phases, phase 1 (the initial 54 patients) and phase 2 (the remaining 336 patients). A significant decrease in the OT (116.8 ± 22.4 vs. 93.8 ± 17.8 min; p < 0.001) and complication rate (16.7 vs. 5.7%; p < 0.01) including the rate of bile leakage (7.4 vs. 1.5%; p < 0.01) and retained stone (3.7 vs. 0.3%; p < 0.01) was observed between the two phases. In addition, 20 patients had conversion to open surgery. Impacted stones were independently associated with conversion, as indicated by a multivariable analysis. CONCLUSION: The data suggest that the learning curve of this procedure was achieved in approximately 54 cases. An impacted stone was the only risk factor that affected the conversion rate.

Speckle-Type POZ Protein Down-Regulates Matrix Metalloproteinase 2 Expression via Sp1/PI3K/Akt Signaling Pathway in Colorectal Cancer.

BACKGROUND: Elevated expression of matrix metalloproteinases (MMPs) is correlated with invasion and metastasis of colorectal cancer (CRC). Recently, a previous study has suggested that speckle-type POZ protein (SPOP) could inhibit cancer cell proliferation and migration through down-regulation of MMP2 and MMP7, with a mechanism remaining unknown. AIM: In this study, we, by using both CRC cells and normal colorectal cells, aimed to investigate the causal relationship between SPOP and MMP2, as well as the potential signaling pathways. METHODS: The causal relationship between SPOP and MMP2 was determined by both RT-PCR and Western blot in cells with SPOP expression or siRNA interference. The signaling pathway involved in MMP2 down-regulation by SPOP was subsequently identified by determination on the expression and phosphorylation of key signaling pathway proteins. Transcription factor involving in this MMP2 regulation was identified by determination on expression, phosphorylation, and nuclear translocation of key transcription factors. RESULTS: SPOP overexpression could significantly decrease MMP2 expression, while the knockdown of SPOP, in contrast, resulted in enhanced MMP2 level. Measurement of expression and phosphorylation of key signaling pathway proteins revealed that SPOP could inhibit PI3K and p-Akt level. Further tests on transcription factors showed that SPOP could inhibit SP1 phosphorylation and nuclear translocation. CONCLUSIONS: SPOP could down-regulate MMP2 expression in CRC, and this regulation is mediated by inhibiting SP1 phosphorylation and nuclear translocation through PI3K/Akt signaling pathway. Our findings in this study provide understanding of MMP2 regulation in CRC and may also shed lights on the development of anti-CRC treatments.

Double primary hepatic cancer (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) originating from hepatic progenitor cell: a case report and review of the literature.

BACKGROUND: Synchronous development of primary hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in different sites of the liver have rarely been reported before. The purpose of this study is to investigate the clinicopathological characteristics of synchronous double cancer of HCC and ICC. CASE PRESENTATION: A 56-year-old Chinese man without obvious liver cirrhosis was preoperation diagnosed with multiple HCC in segments VI (SVI) and VII (SVII) by the abdominal computed tomography (CT) and contrast-enhanced ultrasonography (CEUS). We performed hepatic resection of both segments. The tumors in SVI and SVII were pathologically diagnosed as ICC and HCC, respectively. Immunohistochemically, the HCC in SVII was positive for HepPar-1 and negative for CK19, while the ICC in SVI tumor was positive for CK19 and negative for HepPar-1. Interestingly, the immunohistochemical results also showed that the classic hepatic progenitor cell (HPCs) markers CD34 and CD117 were both positive of the two tumors. The patient still survived and at a 1-year follow-up did not show evidence of metastasis or new recurrent lesions. We speculate that the two masses may have originated from HPCs based on the findings of this patient. CONCLUSIONS: Synchronous development of HCC and ICC is very rare with unique clinical and pathological features. The correct preoperative diagnosis of double hepatic cancer of HCC and ICC is difficult. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection were both the independent risk factor to the development of double liver cancer. Hepatic resection is the preferred and most effective treatment choice. The prognosis of synchronous occurrence of double hepatic cancer was poorer than for either HCC or ICC, and the origin of it needs further study.

Rock2 stabilizes ß-catenin to promote tumor invasion and metastasis in colorectal cancer.

Rho-associated coiled-coil-containing protein kinase 2 (Rock2) is an effector for the small GTPase Rho and plays an important role in tumor progression and metastasis. However, the effect of Rock2 in colorectal cancer (CRC) still remains unclear. In this study, we found that Rock2 expression was markedly increased in clinical CRC tissues compared with adjacent non-cancerous tissues. High expression of Rock2 was correlated with tumor metastasis and poor prognosis in CRC. In addition, the knockdown of Rock2 suppressed the invasion and metastasis of CRC cells both in vitro and in vivo. Furthermore, we found that the ß-catenin/TCF4 pathway contributed to the effects of Rock2 in CRC cells, and Rock2 stabilized ß-catenin by preventing its ubiquitination and degradation. Taken together, this novel pathway for ß-catenin control plays a biologically relevant role in CRC metastasis.

Rock2 promotes the invasion and metastasis of hepatocellular carcinoma by modifying MMP2 ubiquitination and degradation.

Rho-associated coiled-coil-containing protein kinase 2 (Rock2) is a downstream effector of Rho that plays an important role in the tumorigenesis and progression of hepatocellular carcinoma (HCC). Matrix metalloproteinase 2 (MMP2) is a master regulator of tumor metastasis. In this study, we investigated the collections of Rock2 and MMP2 in HCCs and determined the potential role and molecular mechanism of Rock2 in MMP2-mediated invasiveness and metastasis. We found that Rock2 and MMP2 were markedly overexpressed in HCCs compared with the corresponding adjacent tissues, where a positive correlation in their expression was found. The knockdown of Rock2 significantly decreased MMP2 expression and inhibited the invasion and metastasis of HCC in vitro and in vivo. Additionally, the upregulation of MMP2 rescued the decreased migration and invasion induced by the knockdown of Rock2, whereas the knockdown of MMP2 decreased Rock2-enhanced HCC migration and invasion. Mechanistically, Rock2 stabilized MMP2 by preventing its ubiquitination and degradation. Together, our results link two drivers of invasion and metastasis in HCC and identify a novel pathway for MMP2 control.

Overexpression of HOXB9 promotes metastasis and indicates poor prognosis in colon cancer.

OBJECTIVE: Homeobox B9 (HOXB9) is proposed to be involved in tumor angiogenesis and metastasis. We investigated the role of HOXB9 in the progression of colon cancer. METHODS: HOXB9 expression was investigated by immunohistochemically and Western blotting in 128 colon cancer patients and the results were analyzed statistically associated with clinicopathological data and survival of the patients. The effect of HOXB9 on cell invasion and metastases abilities were analyzed in vitro and in vivo. RESULTS: HOXB9 is overexpressed in colon cancer tissues and significantly correlated with metastasis and poor survival of patients (P<0.05, respectively). Additionally, high levels of expression of HOXB9 were observed in metastatic lymph nodes. The down-regulation of HOXB9 expression can inhibit the migration and invasive ability of colon cancer cells, while exogenous expression of HOXB9 in colon cancer cells enhanced cell migration and invasiveness. Moreover, stable knockdown of HOXB9 reduced the liver and lung metastasis of colon cancer in vivo. CONCLUSIONS: HOXB9 may play an important role in the invasion and metastasis of colon cancer cells and may be a useful biomarker for metastasis and prognostic of colon cancer.

Deubiquitinase PSMD7 facilitates pancreatic cancer progression through activating Nocth1 pathway via modifying SOX2 degradation.

BACKGROUND: Ubiquitination is a critical post-translational modification which can be reversed with an enzyme family known as deubiquitinating enzymes (DUBs). It has been reported that dysregulation of deubiquitination leads to carcinogenesis. As a member of the DUBs family, proteasome 26 S subunit non-ATPase 7 (PSMD7) serves as an underlying tumour-promoting factor in multiple cancers. However, the clinical significance and biological functions of PSMD7 in pancreatic cancer (PC) remain unclear. RESULTS: In this study, we first reported frequent overexpression of PSMD7 in PC tissues, and high levels of PSMD7 were markedly linked to shorter survival and a malignant phenotype in PC patients. An array of in vitro and in vivo gain/loss-of-function tests revealed that PSMD7 facilitates the progression of PC cells. Additionally, we found that PSMD7 promotes PC cell progression by activating the Notch homolog 1 (Notch1) signalling. Interestingly, in PC cells, the inhibitory effect of PSMD7 knockdown on cellular processes was comparable to that observed upon Notch1 knockdown. Mechanistically, PSMD7 deubiquitinated and stabilised sex determining region Y (SRY)-box 2 (SOX2), a key mediator of Notch1 signalling. The stabilisation of SOX2, mediated by PSMD7, dramatically increased SOX2 protein levels, subsequently activating the Notch1 pathway. Finally, restoration of SOX2 expression abrogated the PSMD7-silenced antitumour effect. CONCLUSIONS: Taken together, our work identifies and validates PSMD7 as a promoter of PC progression through augmentation of the Notch1 signalling pathway mediated by SOX2. This finding suggests that PSMD7 holds promise as a potential therapeutic target for the management of this refractory disease.

Rock2 regulates Cdc25A through ubiquitin proteasome system in hepatocellular carcinoma cells.

Rho-associated coiled-coil containing protein kinase 2 (Rock2) belongs to a family of serine/threonine kinases which are actived via interaction with Rho GTPases. Recently, overexpression of Rock2 has been demonstrated in human hepatocellular carcinoma (HCC), but the potential role of Rock2 in tumorigenesis remains unclear. Cdc25A acts as a key checkpoint during the G1/S phase and has also been found to be overexpressed in HCC. Here, we report that Rock2 regulates cell cycle progression via ubiquitination of Cdc25A in HCC. In HCC tissues, Rock2 and Cdc25A were aberrantly upregulated and revealed a significantly positive correlation. Knockdown of Rock2 inhibited HCC cell growth and promoted cell-cycle arrest at the G1/S phase via regulation of Cdc25A. When cells were exposed to DNA damage, Rock2 increased cell survival by regulating Cdc25A. Co-immunoprecipitation and immunofluorescence analyses indicated that Rock2 regulated Cdc25A via direct binding. Furthermore, knockdown of Rock2 activated Cdc25A ubiquitination and promoted its degradation. Our results defined a role for Rock2 in modulation of Cdc25A ubiquitination, indicating a novel mechanism of Cdc25A regulation and a potential function for Rock2 in the development of HCC.

Identification of molecular subtypes based on PANoptosis-related genes and construction of a signature for predicting the prognosis and response to immunotherapy response in hepatocellular carcinoma.

Background: Previous studies have demonstrated that PANoptosis is strongly correlated with cancer immunity and progression. This study aimed to develop a PANoptosis-related signature (PANRS) to explore its potential value in predicting the prognosis and immunotherapy response of hepatocellular carcinoma (HCC). Methods: Based on the expression of PANoptosis-related genes, three molecular subtypes were identified. To construct a signature, the differentially expressed genes between different molecular subtypes were subjected to multivariate least absolute shrinkage and selection operator Cox regression analyses. The risk scores of patients in the training set were calculated using the signature. The patients were classified into high-risk and low-risk groups based on the median risk scores. The predictive performance of the signature was evaluated using Kaplan-Meier plotter, receiving operating characteristic curves, nomogram, and calibration curve. The results were validated using external datasets. Additionally, the correlation of the signature with the immune landscape and drug sensitivity was examined. Furthermore, the effect of LPCAT1 knockdown on HCC cell behavior was verified using in vitro experiments. Results: This study developed a PANRS. The risk score obtained by using the PANRS was an independent risk factor for the prognosis of patients with HCC and exhibited good prognostic predictive performance. The nomogram constructed based on the risk score and clinical information can accurately predicted the survival probability of patients with HCC. Patients with HCC in the high-risk groups have high immune scores and tend to generate an immunosuppressive microenvironment. They also exhibited a favorable response to immunotherapy, as evidenced by high tumor mutational burden, high immune checkpoint gene expression, high human leukocyte antigen gene expression, low tumor immune dysfunction and low exclusion scores. Additionally, the PANRS enabled the identification of 15 chemotherapeutic agents, including sorafenib, for patients with HCC with different risk levels, guiding clinical treatment. The signature gene LPCAT1 was upregulated in HCC cell lines. LPCAT1 knockdown markedly decreased HCC cell proliferation and migration. Conclusion: PANRS can accurately predict the prognosis and immunotherapy response of patients with HCC and consequently guide individualized treatment.

SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53.

Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer.

Identification of a novel binding protein of FAT10: eukaryotic translation elongation factor 1A1.

BACKGROUND: FAT10 is known to execute its functions mainly through conjugation to different substrates, and these known functions include cytokine responses, apoptosis, mitosis, and tumorigenesis. Nonetheless, the known binding proteins of FAT10 cannot explain all its known functions. As such, the aim of this study was to identify unidentified conjugation proteins of FAT10. METHODS: The yeast two-hybrid system was employed in this study. FAT10 was used as the bait protein for screening of a cDNA library from a human hepatocellular carcinoma cell line, Hep3B. Protein interactions were confirmed based on localization studies and co-immunoprecipitation assays. The expression of mRNA and protein was determined using real-time polymerase chain reaction and western blot analyses, respectively. RESULTS: In this study, we identified eukaryotic elongation factor 1A1 (eEF1A1) as a FAT10-specific binding protein. The binding between FAT10 and eEF1A1 was confirmed both in vivo and in vitro. We also found that, when the expression of FAT10 was reduced by siRNA knockdown, this resulted in downregulation of eEF1A1 expression at both the mRNA and protein levels in human hepatocellular carcinoma cells. CONCLUSIONS: We propose a model in which eEF1A1 serves as a substrate of FAT10 to accomplish, in part, its functions in regulating the biological behavior of tumor cells. Since both eEF1A1 and FAT10 are important for tumorigenesis and development, comprehending the mechanisms of this interaction can provide clues for identification of novel strategic targets for drug screening and molecular typing, and possibly in the development of new effective therapeutic strategies against hepatocellular carcinoma.