Curcumin targets miR-134-5p to suppress the progression of colorectal cancer through regulating the CDCA3/CDK1 pathway.

It has been reported the anti-tumor action of curcumin on colorectal cancer. In this study, we aimed to explore the potential mechanisms underlying curcumin in the development of colorectal cancer. CCK-8, EdU, flow cytometry, and transwell invasion assays were conducted to investigate the function role of curcumin in cell proliferation, apoptosis, and invasion. The level of miR-134-5p and CDCA3 was determined using RT-qPCR analysis. Western blot was applied for detecting the levels of c-myc, MMP9, CDCA3, and CDK1. Dual-luciferase reporter assay was used to evaluate the relationship between miR-134-5p and CDCA3, and IP assay was performed to examine the interaction between CDCA3 and CDK1. Additionally, SW620 cells were injected into the mice to form the xenograft tumor model. Curcumin treatment repressed cell growth and invasion, and induced cell apoptosis in HCT-116 and SW620 cells. Curcumin elevated miR-134-5p expression and restrained CDCA3 expression in HCT-116 and SW620 cells. MiR-134-5p inhibitor or CDCA3 overexpression could restore the effects of curcumin on cell growth, apoptosis, and invasion in HCT-116 and SW620 cells. MiR-134-5p targeted CDCA3, and CDCA3 could rescue the repressive effects of miR-134-5p on the progression of colorectal cancer. Moreover, CDCA3 interacted with CDK1, and CDK1 overexpression blocked the suppressive effects of CDCA3 downregulation on the development of colorectal cancer. In addition, curcumin treatment repressed tumor growth in colorectal cancer via increasing miR-134-5p and downregulating CDCA3 and CDK1 expression in vivo. Our findings provided the evidence that curcumin upregulated miR-134-5p to inhibit the progression of colorectal cancer by regulating CDCA3/CDK1 pathway.

A tumor microenvironment-associated circRNA predictor for tumor relapse and chemotherapy vulnerability in nasopharyngeal carcinoma.

Accurate risk stratification for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is crucial for prognosis and treatment decisions. Here, we develop a tumor microenvironment-associated circular RNA (circRNA) signature that can stratify LA-NPC patients with different risks of relapse and vulnerability to induction chemotherapy (IC). Relapsed-related circRNAs are identified by comparing expression profiles between patients with and without relapse, followed by quantitative validation in the training cohort (n = 170). A nine-circRNA signature is constructed to classify patients into high-risk and low-risk groups. Low-risk patients have significantly favorable clinical survivals, which is validated in the internal (n = 170) and external (n = 150) cohorts. They are characterized by an immune-active microenvironment and can derive benefits from IC. Meanwhile, high-risk patients characterized with pro-relapse and DNA repair-associated features, are vulnerable to chemoresistance. Overall, the circRNA-based classifier serves as a reliable prognostic tool and might guide chemotherapy decisions for patients with LA-NPC.

Curcumin ameliorates oxidized low-density lipoprotein (ox-LDL)-caused damage in human umbilical vein endothelial cells (HUVECs) through the miR-599/MYD88/NF-κB axis.

BACKGROUND: The role of curcumin in multiple human diseases was widely reported, including arteriosclerosis (AS). We aimed to investigate the correlation between curcumin and AS-related microRNAs (miRNAs) to find out more underlying mechanism of curcumin used in AS. METHODS: Cell proliferation and apoptosis were determined using CCK-8 assay, EdU staining assay, flow cytometry, and western blot for the detection of PCNA and Bax protein expression in human umbilical vein endothelial cells (HUVECs). Inflammation response was evaluated using ELISA kits, and oxidative stress was evaluated by detecting SOD activity and MDA level using the matched commercial kits. RT-qPCR analysis was applied for miR-599 and MYD88 mRNA level measurement. RESULTS: Curcumin treatment and miR-599 overexpression could promote cell proliferation, and inhibit cell apoptosis, inflammation response and oxidative stress, thereby alleviating ox-LDL-induced cell damage in HUVECs. Mir-599 was lowly expressed and MYD88 was highly expressed in AS patients and AS cell model. Curcumin could modulate miR-599 to exert the protective effect on ox-LDL-caused cell damage, and miR-599 directly targeted MYD88 to alleviate ox-LDL-caused cell damage in HUVECs. Curcumin targeted miR-599 to regulate MYD88 expression, thereby inactivating the NF-κB pathway in AS cell model. CONCLUSION: Our findings illustrated that curcumin exhibited anti-AS effect through the miR-599/MYD88 axis and thereby inhibiting the NF-κB pathway.

Proteomic profiling identifies novel diagnostic biomarkers and molecular subtypes for mucinous tubular and spindle cell carcinoma of the kidney.

Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare renal epithelial neoplasm resembling type 1 papillary renal cell carcinoma (PRCC) morphologically and immunohistochemically. The accurate diagnosis of MTSCC remains a challenge. Here, by using proteomic profiling, we characterized MTSCC and PRCC to identify diagnostic biomarkers. We found that the MTSCC tumor proteome was significantly enriched in B-cell-mediated immunity when compared with the proteome of adjacent normal tissues of MTSCC or tumors of PRCC. Importantly, we identified MZB1, VCAN, and SOSTDC1 as diagnostic biomarkers to distinguish MTSCC from the solid variant of type 1 PRCC, with an AUC of 0.985 when combined. MZB1 was inversely correlated with tumor clinical stage and may play an anti-tumor role by activating the complement system. Finally, unsupervised clustering revealed two molecular subtypes of MTSCC, displaying different morphology, expression signatures of oxidative phosphorylation, and aggravation. In summary, our analyses identified a three-protein diagnostic panel and molecular subtypes for MTSCC. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Tumor-stroma ratio (TSR) in non-small cell lung cancer (NSCLC) patients after lung resection is a prognostic factor for survival.

BACKGROUND: In recent years, the tumor-stroma ratio (TSR) has been considered to a new and independent predictive variable for the prognosis of some kinds of neoplasms. The objective of this study was to assess the prognostic significance of the TSR in non-small cell lung cancer (NSCLC). METHODS: A cohort of 261 NSCLC patients who underwent radical surgery of lung cancer were included in the present study. Two independent observers visually estimated the TSR on hematoxylin-eosin (H&E) stained tissue pathological slices. According to the proportion of stroma ≥50% or <50%, We separate the patients into two groups: those with stroma-poor and those with stroma-rich tumors. RESULTS: Both univariate and multivariate analyses disclosed that the TSR was associated with overall survival (OS) [hazard ratio (HR), 1.741; 95% confidence intervals (CI), 1.040-2.913 and HR, 1.904; 95% CI, 1.132-3.202, respectively]. The HR values for disease-free survival (DFS) were 1.795 (95% CI, 1.073-3.005) and 2.034 (95% CI, 1.210-3.420). The OS and DFS of patients with stroma-poor tumors were better than those with stroma-rich tumors. CONCLUSIONS: These results demonstrated that the TSR is a new prognostic factor for NSCLC. Stroma-poor tumors were associated with longer disease-free period and better prognosis than were stroma-rich tumors in NSCLC patients. The TSR may contribute to the development of individualized treatment for NSCLC in the future.

Responses to Crizotinib therapy in five patients with non-small-cell lung cancer who tested FISH negative and Ventana immunohistochemistry positive for ALK fusions.

AIM: Although immunohistochemistry (IHC) and reverse transcription-PCR can detect ALK rearrangements, the ALK break-apart FISH assay is currently considered the standard method. MATERIALS & METHODS: Five patients with advanced non-small-cell lung cancer, who had an ALK-negative FISH result that was later confirmed as positive by the Ventana IHC assay, were studied. Four had previously received chemotherapy or radiotherapy. All five were subsequently treated with Crizoitinib 250 mg twice daily. RESULTS & CONCLUSION: Four patients had a partial response to Crizotinib and one had stable disease. IHC is an efficient technique for diagnosing ALK rearrangements in patients with non-small-cell lung cancer, and may serve as an alternative to FISH in clinical practice.

Vascular invasion as an independent predictor of poor prognosis in nonmetastatic gastric cancer after curative resection.

The prognostic significance of vascular invasion (VI) in nonmetastatic gastric cancer (GC) remains a matter of controversy. The purpose of this study was to assess the impact of VI on survival in this group of GC patients. We enrolled 361 GC patients without metastasis who underwent curative gastrectomy between 1996 and 2009 in Sun Yat-sen University Cancer Center. A retrospective analysis of the clinicopathological data was performed, focusing on the impact of VI detected by routine H&E staining on disease-free survival (DFS) and cancer-specific survival (CSS). The presence of VI was detected in 13.9% of our cohort. The VI status was significantly correlated with the tumor size, infiltration depth, and TNM stage (P < 0.05). Patients with VI showed significantly lower DFS and CSS compared with patients without VI (P < 0.0001 for both). The subgroup analysis indicated that the presence of VI was a negative predictor of DFS in all TNM stages and a predictor of lower CSS only in stage I (P < 0.05 for all). A multivariate Cox proportional analysis identified VI as an independent predictor of CSS (P = 0.022). The presence of VI is a risk factor for recurrence and an independent predictor of poor survival in nonmetastatic GC after curative resection. The VI status should be considered to stratify with this group of GC patients for adjuvant treatment and more effective follow-up protocol.

The prognostic significance of lymphovascular invasion in patients with resectable gastric cancer: a large retrospective study from Southern China.

BACKGROUND: The focus of this study was to assess the impact of lymphovascular invasion (LVI) on both the recurrence of cancer and the long-term survival of Chinese patients with resectable gastric cancer (GC). METHODS: A retrospective analysis of the clinicopathological data for 1148 GC patients who had undergone gastrectomy with regional lymphadenectomy was performed. The primary objective was to assess the correlation between LVI and post-surgery outcomes for each patient. This was done by routine H & E staining for LVI on patients' disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: LVI was detected in 404 (35.2%) of the 1148 GC patients. The presence of LVI was significantly correlated with the level of CA19-9, the tumor size, the Lauren classification, tumor differentiation, gastric wall invasive depth, lymph node involvement, distant metastasis and an advanced TNM stage. There was a lower DFS and DSS in the patients with LVI as compared to the patients without LVI. A multivariate analysis also identified LVI as an independent prognostic factor of both DSS and DFS. CONCLUSIONS: The presence of LVI is a risk factor for the recurrence of cancer and an independent indicator of a poor outcome in GC patients following surgery. The LVI status should be taken into consideration when determining the best approach for the treatment of the individual.

The prognostic significance of tyrosine-protein phosphatase nonreceptor type 12 expression in nasopharyngeal carcinoma.

Tyrosine-protein phosphatase nonreceptor type 12 (PTPN12) has been proposed to predict prognosis of various human cancers. However, the clinicopathologic and prognostic significance of PTPN12 expression in NPC has not yet been elucidated. The objective of this study was to investigate the clinicopathological and prognostic implication of PTPN12 in nasopharyngeal carcinoma (NPC) patients. Protein expression levels of PTPN12 were explored by semiquantitative immunohistochemical staining on archival formalin-fixed, paraffin-embedded pathological specimens consisting of 203 NPCs, and 40 normal nasopharyngeal mucosa tissues. Receiver operating characteristic (ROC) curve analysis was employed to determine the cutoff score of PTPN12 expression in NPCs. The PTPN12 immunohistochemical staining results were then correlated with various clinicopathological features and patients' prognosis using various statistical models. Our results showed that decreased expression of PTPN12 was more frequently observed in NPC tissues compared with the normal nasopharyngeal mucosa. Further correlation analyses indicated that the decreased expression of PTPN12 was significantly associated with tumor T classification, N classification, distant metastasis, and clinical stage in NPCs (P < 0.05). Univariate analysis showed a significant association between the decreased expression of PTPN12 and adverse overall survival and disease-free survival (P < 0.05). More importantly, multivariate analysis identified the PTPN12 expression in NPC as an independent prognostic factor. The decrease expression of PTPN12 might be important in conferring a more aggressive behavior in NPC. Thus, PTPN12 expression may be used as a novel independent prognostic biomarker for patients with NPC.

Pseudoepitheliomatous hyperplasia mimicking invasive squamous cell carcinoma in extranodal natural killer/T-cell lymphoma: a report of 34 cases.

AIMS: Pseudoepitheliomatous hyperplasia (PEH) is defined as a pattern of epidermal reaction. However, it has not yet been extensively documented in extranodal natural killer/T-cell lymphoma (ENKTL). The aim of our study was to analyse a series of ENKTLs concomitant with PEH mimicking squamous cell carcinoma (SCC). METHODS AND RESULTS: We analysed 34 cases of ENKTL with PEH. In our study, the incidence of PEH was 3.8% in ENKTLs diagnosed over a 13-year period. All 34 cases presented with PEH, appearing as tongue-like projections of squamous epithelium into the underlying submucosa/dermis with variable depths and jagged borders. The keratinocytes sometimes showed a minor degree of cytological atypia, mostly in the stratum basale, and keratinocyte necrosis was absent. Atypical mitoses and a high nuclear/cytoplasmic ratio were absent. The submucosa and the squamous cell cords were also permeated by atypical lymphocytes. CONCLUSIONS: ENKTL can be associated with PEH, and the atypical lymphoid cell population can be highly subtle, and therefore may be easily mistaken for SCC, leading to inappropriate therapy. A correct diagnosis requires awareness and recognition of this pitfall by recognizing the associated conditions listed above, which distinguish PEH from SCC.

Prognostic significance of the pN classification supplemented by vascular invasion for esophageal squamous cell carcinoma.

BACKGROUND: The biological behavior and clinical outcome of esophageal squamous cell carcinoma (ESCC) are difficult to predict. METHODOLOGY/PRINCIPAL FINDINGS: We investigate the prognostic impact of vascular invasion to establish a risk stratification model to predict recurrence and overall survival. We retrospectively evaluated the vascular invasion of 433 patients with ESCC treated with surgery between 2000 and 2007 at a single academic center. Those patients were assigned to a testing cohort and a validation cohort by random number generated in computer. The presence of vascular invasion was observed in 113 of 216 (52.3%) and 96 of 217 (44.2%) of ESCC in the training and validation cohorts, respectively. Further correlation analysis demonstrated that vascular invasion in ESCC was significantly correlated with more advanced pN classification and stage in both cohorts (P<0.05). Additionally, presence of vascular invasion in ESCC patients was associated closely with poor overall and recurrence-free survival as evidenced by univariate and multivariate analysis in both cohorts (P<0.05). In the subset of ESCC patients without lymph node metastasis, vascular invasion was evaluated as a prognostic predictor as well (P<0.05). More importantly, the combined prognostic model with pN classification supplemented by vascular invasion can significantly stratify the risk (low, intermediate and high) for overall survival and recurrence-free survival in both cohorts (P<0.05). The C-index to the combined model showed improved predictive ability when compared to the pN classification (0.785 vs 0.739 and 0.689 vs 0.650 for the training and validation cohorts, respectively; P<0.05). CONCLUSIONS/SIGNIFICANCE: The examination of vascular invasion could be used as an additional effective instrument in identifying those ESCC patients at increased risk of tumor progression. The proposed new prognostic model with the pN classification supplemented by vascular invasion might improve the ability to discriminate ESCC patients' outcome.

Anti-hyperuricemic and nephroprotective effects of Modified Simiao Decoction in hyperuricemic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Modified Simiao Decoction (MSD), based on clinical experience, has been used for decades and famous for its efficiency in treating hyperuricemic and gouty diseases. AIM OF THE STUDY: To investigate the effects of MSD on anti-hyperuricemic and nephroprotective effects are involved in potassium oxonate-induced hyperuricemic mice. MATERIALS AND METHODS: The effects of MSD were investigated in hyperuricemic mice induced by potassium oxonate. MSD were fed to hyperuricemic mice daily at a dose of 0.45, 0.90, 1.80 g/kg for 10 days, and allopurinol (5mg/kg) was given as a positive control. Serum and urine levels of uric acid and creatinine, and fractional excretion of uric acid (FEUA) were determined by colorimetric method. Its nephroprotective effects were evaluated by determining a panel of oxidative stress markers after the intervention in hyperuricemic mice. Simultaneously, protein levels of urate transporter 1 (URAT1) and organic anion transporter 1 (OAT1) in the kidney were analyzed by Western blotting. RESULTS: MSD could inhibit XOD activities in serum and liver, decrease levels of serum uric acid, serum creatinine and BUN, and increased levels of urine uric acid, urine creatinine, FEUA dose-dependently through down-regulation of URAT1 and up-regulation of OAT1 protein expressions in the renal tissue of hyperuricemic mice. It also effectively reversed oxonate-induced alterations on renal MDA levels and SOD activities in this model. CONCLUSION: MSD processes uricosuric and nephroprotective actions by regulating renal urate transporters and enhancing antioxidant enzymes activities to improve renal dysfunction in hyperuricemic mice.

Possible role of toll-like receptor 4 in acute pancreatitis.

Because the mechanism underlying the development of acute pancreatitis (AP) has not yet been fully clarified, it has been a hot but difficult topic in basic and clinical research for a long time. Currently, the dominant hypothesis for the pathogenesis of AP is that it is a disease of self-digestive acute chemical inflammation induced by trypsin activation. As proteins to trigger the inflammatory response cascade, Toll-like receptors (TLRs), especially TLR4, provide a new clue for studying the pathogenesis of AP from the source. Some studies have found that when TLR4 is activated by certain factors, it can amplify an inflammatory effect and aggravate the body's inflammatory response through a series of signal transduction. Toll-like receptor 4 may play an important role in the synthesis and release of proinflammatory cytokines, and the up-regulation of the TLR4 gene may be related with the development and progression of multiple organ injury during AP. As the "gate" of inflammatory response, TLR4 may be closely associated with the development and progression of multiple organ injury during AP. Understanding the roles of TLR4 in AP will help to further clarify the pathogenesis of AP and to search a new target for the treatment of AP.

Effect of salvia miltiorrhizae on the expressions of TLR4 protein in the liver of rats with SAP or OJ.

To investigate the effect of salvia miltiorrhizae on the expressions of TLR4 protein in the liver of rats with severe acute pancreatitis (SAP) and obstructive jaundice (OJ), and explore the protective mechanism of salvia miltiorrhizae on the liver of rats. A total of 288 mice was used in SAP- (n = 108) and OJ-associated experiments (n = 180). The rats were randomly divided into sham-operated, model control and treated group. Based on the different time points after operation, these groups were subdivided into 3, 6 and 12 h subgroups (SAP rats, n = 12) or 7, 14, 21 and 28 days subgroups (OJ rats, n = 15). At the corresponding time points after operation, blood and liver specimens were collected to determine the contents of endotoxin and TNF-alpha in the blood as well as the expression levels of TLR4 protein in the liver. Compared with the corresponding model control group, though the number of dead SAP or OJ rats in the treated group declined, no statistical difference was noted; The levels of plasma endotoxin in SAP (at 6 and 12 h) or OJ rats in the treated group decreased significantly (P < 0.001 and P < 0.01, respectively); The levels of serum TNF-alpha in SAP (at 12 h) or OJ rats (on 14 days) declined (P < 0.001 and P < 0.01, respectively); The staining intensity as well as the product of staining intensity and positive rate of TRL4 protein only significantly declined on 7 and 28 days in OJ rats (P < 0.01). On 7 days, treated group in positive rate of TLR4 protein were significantly lower than that in model control group (P < 0.01). The pathological changes in different treated groups of SAP and OJ rats were improved. Salvia miltiorrhizae is able to reduce the levels of plasma endotoxin and inhibit effectively the expressions of TLR4 protein in the liver of SAP or OJ rats, thereby decreasing inflammatory reaction and exerting protective effect on liver function.