Survival benefits of para-aortic lymphadenectomy in colorectal cancer with clinically suspected para-aortic lymph node metastasis: a meta-analysis and systematic review.

BACKGROUND AND OBJECTIVES: In patients with colorectal cancer and clinically suspected para-aortic lymph node metastasis, the survival benefit of para-aortic lymphadenectomy is unknown. We conducted a meta-analysis and systematic review to investigate it. METHODS: PubMed, Web of Science, and EMBASE were searched until January 2000 to April 2022 to identify studies reporting overall survivals, complication rates, and hazard ratios of prognostic factors in patients with colorectal cancer undergoing para-aortic lymphadenectomy, and those data were pooled. RESULTS: Twenty retrospective studies (1021 patients undergoing para-aortic lymphadenectomy) met the inclusion criteria. Meta-analysis indicates that participants undergoing para-aortic lymphadenectomy were associated with 5-year survival benefit, compared to those not receiving para-aortic lymphadenectomy (odds ratio = 3.73, 95% confidence interval: 2.05-6.78), but there was no significant difference in complication rate (odds ratio = 0.97, 95% confidence interval: 0.46-2.08). Further analysis of para-aortic lymphadenectomy group showed that 5-year survival of the positive group with pathologically para-aortic lymph node metastasis was lower than that of the negative group (odds ratio = 0.19, 95% confidence interval: 0.11-0.31). Moreover, complete resection (odds ratio = 5.26, 95% confidence interval: 2.02-13.69), para-aortic lymph node metastasis (≤4) (hazard ratio = 1.88, 95% confidence interval: 0.97-3.62), and medium-high differentiation (hazard ratio = 2.98, 95% confidence interval: 1.48-5.99) were protective factors for survival. Preoperative extra-retroperitoneal metastasis was associated with poorer relapse-free survival (hazard ratio = 1.85, 95% confidence interval: 1.10-3.10). CONCLUSION: Para-aortic lymphadenectomy had promising clinical efficacy in prolonging survival rather than complication rate in patients with colorectal cancer and clinically diagnostic para-aortic lymph node metastasis. Further prospective studies should be performed. TRIAL REGISTRATION: PROSPERO: CRD42022379276.

Aggressive hydration compared to standard hydration with lactated ringer's solution for prevention of post endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND AND AIMS: Previous studies have suggested that aggressive hydration with lactated ringer solution are one of the protective factors in preventing post endoscopic retrograde cholangiopancreatography (post-ERCP). We conducted a systematic review and meta-analysis to examine the efficacy aggressive hydration with lactated Ringer solution in preventing PEP. METHODS: All published and unpublished articles on aggressive hydration with lactated ringer solution in those underwent ERCP procedure for any reasons were screened for eligibility. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. This paper doesn't need the IRB approval. RESULTS: Seven RCTs met the inclusion criteria. Meta-analysis indicates that aggressive hydration with lactated Ringer solution were associated with lower PEP rate.[odds ratio (OR) 0.29; 95% confidence interval (CI) 0.18-0.48]; lower incidence of hyperamylasemia (OR 0.49; 95% CI 0.35, 0.69) and lower risk of pain (OR 0.28; 95% CI 0.10-0.81). The association between aggressive hydration with lactated Ringer solution and incidence of moderate severity PEP were unclear (OR 0.57; 95% CI 0.22, 1.45). Sensitivity analyses also showed that omitting 1 study from analysis of PEP rate could reduce the heterogeneity but did not change the conclusion of this meta-analysis. A cumulating meta-analysis was performed statistically which showed a stable result of overall incidence of PEP. CONCLUSIONS: Aggressive hydration with lactated Ringer solution was a protective factor in reducing the overall incidence of PEP, hyperamylasemia and risk of abdominal pain.

Non-coding RNAS and colorectal cancer liver metastasis.

More than 50% of colorectal cancer (CRC) deaths are attributed to metastasis, and the liver is the most common distant metastatic site of CRC. The molecular mechanisms underlying CRC liver metastasis are very complicated and remain largely unknown. Accumulated evidence has shown that non-coding RNAs (NcRNAs) play critical roles in tumor development and progression. Here we reviewed the roles and underlying mechanisms of NcRNAs in CRC liver metastasis.

circRNA and gastrointestinal cancer.

Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs that form covalently closed continuous loops without 3' end poly (A) tails and 5' end caps. circRNAs are more conservative and stable than linear RNA. circRNAs can specifically bind to microRNAs as competing endogenous RNA, thereby directly or indirectly regulating the expression of related genes. circRNAs have been implicated in several cancers including gastrointestinal (GI) cancers. Some circRNAs have the potential to become biological biomarkers and therapeutic targets of GI cancers. However, the multiple functional roles of circRNAs in GI cancers remain largely unclear.

PIK3CD induces cell growth and invasion by activating AKT/GSK-3ß/ß-catenin signaling in colorectal cancer.

The catalytic subunit p110δ of phosphoinositide 3-kinase (PI3K) encoded by PIK3CD has been implicated in some human solid tumors. However, its roles in colorectal cancer (CRC) remain largely unknown. Here we found that PIK3CD was overexpressed in colon cancer tissues and CRC cell lines and was an independent predictor for overall survival (OS) of patients with colon cancer. The ectopic overexpression of PIK3CD significantly promoted CRC cell growth, migration and invasion in vitro and tumor growth in vivo. In contrast, inhibition of PIK3CD by specific small-interfering RNA or idelalisib dramatically suppressed CRC cell growth, migration and invasion in vitro and tumor growth in vivo. Moreover, PIK3CD overexpression increased AKT activity, nuclear translocation of ß-catenin and T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activity and decreased glycogen synthase kinase 3ß (GSK-3ß) activity, whereas PIK3CD inhibition exhibited the opposite effects. Furthermore, PIK3CD-mediated cell growth, migration and invasion were reversed by blockade of AKT signaling or depletion of ß-catenin. In addition, PIK3CD expression in colon cancer tissues positively correlated with ß-catenin abnormal expression, which was an independent predictor for OS of colon cancer patients. Taken together, our findings demonstrate that PIK3CD is an independent prognostic factor in CRC and that PIK3CD induces CRC cell growth, migration and invasion by activating AKT/GSK-3ß/ß-catenin signaling, suggesting that PIK3CD might be a novel prognostic biomarker and a potential therapeutic target for CRC.

Interval colorectal cancer: a challenging field in colorectal cancer.

Accumulated evidence has shown that colonoscopy may not be a perfect tool in screening and reducing the incidence of the colorectal cancer (CRC), because interval CRC (I-CRC), a specific subgroup of CRCs, has been challenging the traditional detection technology in recent years. I-CRC is accounting for an increasing proportion in CRCs. However, the effective procedures to prevent and supervise I-CRC need to be explored. In this review, we summarized the incidence, causes, risk factors, characteristics and management of I-CRC. It would promote the awareness of the special value in the education and training for the gastroenterologists, which plays an important role in conquering CRC.

Risk Factors Associated with Intraoperative Major Blood Loss during Resection of Hepatocellular Carcinoma.

BACKGROUND/AIMS: Intraoperative blood loss is an independent predictor of recurrence and survival after resection of hepatocellular carcinoma (HCC). The aim of this study was to identify the risk factors associated with intraoperative major blood loss in patients undergoing liver resection for HCC. METHODOLOGY: Clinicopathologic data and perioperative outcomes of 386 patients who underwent liver resection for HCC were retrospectively reviewed. The patients were divided into high (> 1,000 mL) and low (51,000 mL) blood loss groups according to the intraoperative blood loss. Intraoperative blood loss,more than 1,000 mL was defined as major blood loss. The risk factors associated with intraoperative major blood loss were analyzed by univariate and multivariate analyses. RESULTS: Vascular invasion, major hepatectomy and prolonged operation time were risk factors associated with intraoperative major blood loss during resection of HCC on multivariate analysis. Moreover, HCC patients with intraoperative major blood loss had prolonged hospital stay, higher incidence of postoperative complication and mortality compared with patients' with blood loss 1,000 mL. CONCLUSIONS: Vascular invasion, major hepatectomy and prolonged operation time are independent predictors of intraoperative major blood loss during resection of HCC.

Down-regulation of Gli-1 inhibits hepatocellular carcinoma cell migration and invasion.

Glioma-associated oncogene homolog-1 (Gli-1) is considered a marker of Hedgehog pathway activation and is associated with the progression of several cancers. We have previously reported that Gli-1 was correlated with invasion and metastasis in hepatocellular carcinoma (HCC). However, the exact roles and mechanisms of Gli-1 in HCC invasion are unclear. In this study, we found that small interfering RNA mediated down-regulation of Gli-1 expression significantly suppressed adhesion, motility, migration, and invasion of both SMMC-7721 and SK-Hep1 cells. Furthermore, down-regulation of Gli-1 significantly reduced expressions and activities of both matrix metalloproteinase (MMP)-2 and MMP-9. In addition, we found that down-regulation of Gli-1 resulted in up-regulation of E-cadherin and concomitant down-regulation of Snail and Vimentin, consistent with inhibition of epithelial-mesenchymal transition (EMT). Taken together, our results suggest that down-regulation of Gli-1 suppresses HCC cell migration and invasion likely through inhibiting expressions and activations of MMP-2, 9 and blocking EMT.

Sonic hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/AKT signaling-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9 in liver cancer.

The aberrant activation of sonic hedgehog (SHH) pathway contributes to initiation and progression of various malignancies. However, the roles and underlying mechanisms of SHH signaling pathway in invasion and metastasis of liver cancer have not been well understood. In this study, we found that SHH signaling was activated and correlated with invasion and metastasis in hepatocellular carcinoma (HCC). Enhanced SHH signaling by recombinant human SHH N-terminal peptide (rSHH-N) promoted hepatoma cell adhesion, migration and invasion, whereas blockade of SHH signaling with SHH neutralizing antibody or cyclopamine suppressed hepatoma cell adhesion, migration and invasion. Furthermore, matrix metalloproteinase (MMP)-2 and MMP-9 expressions and activities were upregulated and downregulated by rSHH-N and SHH signaling inhibitor, respectively. The rSHH-N-mediated hepatoma cell migration and invasion was blocked by MMP-specific inhibitors or neutralizing antibodies to MMP-2 and MMP-9. In addition, phosphorylations of AKT and focal adhesion kinase (FAK) were increased and decreased by rSHH-N and SHH signaling inhibitor, respectively. Further investigations showed that activation of AKT and FAK were required for rSHH-N-mediated upregulation of MMP-2 and MMP-9, cell migration and invasion. Finally, we found that SHH protein expression was positively correlated with phosphorylatd FAK Tyr397, phosphorylatd AKT Ser473, MMP-2 and MMP-9 protein expressions in HCC samples. Taken together, our findings suggest that SHH pathway induces cell migration and invasion through FAK/AKT signaling-mediated MMP-2 and MMP-9 production and activation in liver cancer.

Application of immune checkpoint inhibitors in immunotherapy for gastric cancer.

Gastric cancer is the fifth most common cancer worldwide. With the development of immunotherapy, especially the application of immune checkpoint inhibitors (ICIs), the prognosis of advanced gastric cancer has improved. At present, ICIs combined with other therapies or dual ICI strategies in the treatment of advanced gastric cancer have shown clinical effectiveness and controllable safety. In addition, predictive biomarkers facilitate the precise selection of patients. Therefore, it is crucial to explore rational combinations and reliable predictive biomarkers for ICI therapy. This article reviews the recent advances in ICIs and relevant predictive biomarkers in the treatment of gastric cancer.

In recent years, with the application of immunotherapy, clinical efficacy in gastric cancer has been effectively improved. At present, it is encouraging that immunotherapy combined with chemotherapy has become the first choice for the treatment of patients with advanced gastric cancer. However, researchers remain committed to exploring the efficacy of immunotherapy in combination with various therapies. Equally important, the identification of biomarkers can facilitate the selection of patients suitable for immunotherapy. This article summarizes important immunotherapy clinical trials and discusses therapeutic combinations and biomarkers being explored.

Clinicopathologic characteristics and surgical outcomes of hepatocellular carcinoma with portal vein tumor thrombosis.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high predilection for portal vein invasion. Furthermore, the treatment of HCC with portal vein tumor thrombosis (PVTT) is controversial. The objective of this study was to investigate clinicopathologic characteristics and surgical outcomes of HCC patients with PVTT. METHODS: The clinicopathologic data and surgical outcomes of 88 patients HCC with PVTT and 211 patients without PVTT who underwent surgery were retrospectively reviewed. The risk factors and the prognosis of HCC patients with PVTT were determined. RESULTS: Cirrhosis, serum alkaline phosphatase (ALP) > 100 IU/L, tumor size > 8 cm, incomplete tumor capsule, and adjacent organ invasion were risk factors for PVTT in HCC on multivariate analysis. Furthermore, HCC patients with PVTT received more major hepatectomies, had more intraoperative blood loss and greater blood transfusion requirements, and higher incidence of postoperative mortality compared with HCC patients without PVTT. The median overall survival of HCC patients with PVTT after surgery was 9 mo, with the 1-, 2-, and 3-y overall survival rates of 31.1%, 18.3%, and 15.2 %, respectively. AFP level, adjacent organ invasion, and PVTT location predicted overall survival of HCC patients with PVTT. CONCLUSIONS: High serum ALP level, cirrhosis, large tumor, incomplete tumor capsule and adjacent organ invasion are predictors of PVTT in HCC. Surgery is a valid therapy for selected HCC patients with PVTT.

miR-338-3p suppresses invasion of liver cancer cell by targeting smoothened.

MicroRNAs are involved in human carcinogenesis and cancer progression. Our previous study has shown that loss of miR-338-3p expression is associated with clinical aggressiveness of hepatocellular carcinoma (HCC). However, the exact roles and mechanisms of miR-338-3p remain unknown in HCC. To determine whether and how miR-338-3p influences liver cancer cell invasion, we studied miR-338-3p in the liver cancer cell lines, and we found that miR-338-3p is down-regulated in treated cells. Forced expression of miR-338-3p in SK-HEP-1 cells suppressed cell migration and invasion, whereas inhibition of miR-338-3p in SMMC-7721 cells induced cell migration and invasion. Furthermore, smoothened (SMO) was identified as a direct target of miR-338-3p. Forced expression of miR-338-3p down-regulated SMO and matrix metalloproteinase (MMP)-9 expression, but inhibition of miR-338-3p up-regulated SMO and MMP9 expression. However, small interfering RNA targeted SMO reversed the effects induced by blockade of miR-338-3p. SMO and MMP9 were overexpressed and associated with invasion and metastasis in HCC tissues. These data indicate that miR-338-3p suppresses cell invasion by targeting the smoothened gene in liver cancer in vitro and miR-338-3p might be a novel potential strategy for liver cancer treatment.

The Expression of PPAR Pathway-Related Genes Can Better Predict the Prognosis of Patients with Colon Adenocarcinoma.

The postoperative survival time and quality of life of patients with colon adenocarcinoma (COAD) varies widely. In order to make accurate decisions after surgery, clinicians need to distinguish patients with different prognostic trends. However, we still lack effective methods to predict the prognosis of COAD patients. Accumulated evidences indicated that the inhibition of peroxisome proliferator-activated receptors (PPARs) and a portion of their target genes were associated with the development of COAD. Our study found that the expression of several PPAR pathway-related genes were linked to the prognosis of COAD patients. Therefore, we developed a scoring system (named PPAR-Riskscore) that can predict patients' outcomes. PPAR-Riskscore was constructed by univariate Cox regression based on the expression of 4 genes (NR1D1, ILK, TNFRSF1A, and REN) in tumor tissues. Compared to typical TNM grading systems, PPAR-Riskscore has better predictive accuracy and sensitivity. The reliability of the system was tested on six external validation datasets. Furthermore, PPAR-Riskscore was able to evaluate the immune cell infiltration and chemotherapy sensitivity of each tumor sample. We also combined PPAR-Riskscore and clinical features to create a nomogram with greater clinical utility. The nomogram can help clinicians make precise treatment decisions regarding the possible long-term survival of patients after surgery.

Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP-9.

AIM: To investigate the status of Phosphatidylinositol 3-kinase (PI3K)/PTEN/AKT/mammalian target of rapamycin (mTOR) pathway and its correlation with clinicopathological features and matrix metalloproteinase-2, -9 (MMP-2, 9) in human hepatocellular carcinoma (HCC). METHODS: PTEN, Phosphorylated AKT (p-AKT), Phosphorylated mTOR (p-mTOR), MMP-2, MMP-9 and Ki-67 expression levels were evaluated by immunohistochemistry on tissue microarrays containing 200 HCCs with paired adjacent non-cancerous liver tissues. PTEN, MMP-2 and MMP-9 mRNA levels were determined by real-time RT-PCR in 36 HCCs. The relationships between PI3K/PTEN/AKT/mTOR pathway and clinicopathological factors and MMP-2, 9 were analyzed in HCC. RESULTS: In HCC, PTEN loss and overexpression of p-AKT and p-mTOR were associated with tumor grade, intrahepatic metastasis, vascular invasion, TNM stage and high Ki-67 labeling index (P < 0.05). PTEN loss was correlated with p-AKT, p-mTOR and MMP-9 overexpression. Furthermore, PTEN and MMP-2, 9 mRNA levels were down-regulated and up-regulated in HCC compared with paired non-cancerous liver tissues, respectively (P < 0.01). PTEN, MMP-2 and MMP-9 mRNA levels were correlated with tumor stage and metastasis. There was an inverse correlation between PTEN and MMP-9 mRNA expression. However, PI3K/PTEN/AKT/mTOR pathway was not correlated with MMP-2. CONCLUSIONS: PI3K/PTEN/AKT/mTOR pathway, which is activated in HCC, is involved in invasion and metastasis through up-regulating MMP-9 in HCC.

Bead-based microarray analysis of microRNA expression in hepatocellular carcinoma: miR-338 is downregulated.

AIM: Recent studies have underlined causative links between microRNA (miRNA) deregulation and cancer development. However, the relevance of abnormally expressed miRNA to tumor biology has not been well understood in hepatocellular carcinoma (HCC). METHODS: A bead-based miRNA expression profiling method was performed on 20 pairs of surgically removed HCC and adjacent non-tumorous tissue (NT). Special miR-338 downregulations and miR-338 associated with clinical characteristics was validated in an extended samples set of 36 paired HCC and adjacent non-tumorous liver tissues by real-time reverse transcription polymerase chain reaction (RT-PCR) analysis. RESULTS: Out of our bead-based microarray data, 12 upregulated and 19 downregulated miRNA were found to be associated with HCC. Further characterization of miRNA-338, in which 20 pairs of the samples were clustered clearly into two groups according to expression of miR-338, revealed that the level of miR-338 expression can be associated with clinical aggressiveness, such as, tumor size, tumor-node-metastasis stage, vascular invasion and intrahepatic metastasis. These results were validated by real-time RT-PCR analysis. CONCLUSION: Our study suggests that miRNA expression could have relevance to the clinical behavior of HCC and that the bead-based miRNA expression profiling method might be a suitable system to assay miRNA expression in large-scale diagnostic trails.

Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPARgamma signaling pathway.

AIM: Resistance to 5-fluorouracil (5-FU) is a major cause of chemotherapy failure in advanced hepatocellular carcinoma (HCC). Rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, has a crucial role in growth inhibition and induction of apoptosis in several carcinoma cell lines. In this study, we examine rosiglitazone-induced sensitization of HCC cell lines (BEL-7402 and Huh-7 cells) to 5-FU. METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to evaluate cell viability. Western blotting analysis was performed to detect the protein expression (PPARgamma, PTEN, and COX-2) in BEL-7402 cells. Immunohistochemistry staining was used to examine the expression of PTEN in 100 advanced HCC tissues and paracancerous tissues. In addition, small interfering RNA was used to suppress PPARgamma, PTEN, and COX-2 expression. RESULTS: Rosiglitazone facilitates the anti-tumor effect of 5-FU in HCC cell lines, which is mediated by the PPARgamma signaling pathway. Activation of PPARgamma by rosiglitazone increases PTEN expression and decreases COX-2 expression. Since distribution of PTEN in HCC tissues is significantly decreased compared with the paracancerous tissue, over-expression of PTEN by rosiglitazone enhances 5-FU-inhibited cell growth of HCC. Moreover, down-regulation of COX-2 is implicated in the synergistic effect of 5-FU. CONCLUSION: Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-FU antitumor activity through the activation of PPARgamma. The results suggest potential novel therapies for the treatment of advanced liver cancer.

Octreotide inhibits growth of colonic cancer SW480 cells by modulating the Wnt/P-catenin pathway.

Somatostatin can suppress the growth of various tumor cells including colonic cancer. Activated Wnt/ beta-catenin signaling pathway plays a critical role in tumorgenesis and development of colorectal cancer. However, the effect of somatostatin on Wnt/beta-catenin signaling pathway remains unknown. Thus, we investigated the effect of octreotide on Wnt/beta-catenin signaling pathway in human colonic cancer cell SW480. The results of 3-(4,5-imethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) and flow cytometric assays showed that octreotide inhibited growth, induced apoptosis and arrested the G1 cell cycle of SW480 cells in a dose-dependent manner. We demonstrated that octreotide significally up-regulated and down-regulated 13 genes and 17 genes in Wnt/beta-catenin signaling using microarray, respectively. Furthermore, as evidenced by western blot, beta-catenin protein level decreased, whereas phosphorylated beta-catenin protein level increased under octreotide. The present study reveals that octreotide can inhibit human colonic cancer cell growth through inhibition of Wnt/beta-catenin signaling pathway.

Effect of clonal integration on nitrogen cycling in rhizosphere of rhizomatous clonal plant, Phyllostachys bissetii, under heterogeneous light.

Clonal integration plays an important role in clonal plant adapting to heterogeneous habitats. It was postulated that clonal integration could exhibit positive effects on nitrogen cycling in the rhizosphere of clonal plant subjected to heterogeneous light conditions. An in-situ experiment was conducted using clonal fragments of Phyllostachys bissetii with two successive ramets. Shading treatments were applied to offspring or mother ramets, respectively, whereas counterparts were treated to full sunlight. Rhizomes between two successive ramets were either severed or connected. Extracellular enzyme activities and nitrogen turnover were measured, as well as soil properties. Abundance of functional genes (archaeal or bacterial amoA, nifH) in the rhizosphere of shaded, offspring or mother ramets were determined using quantitative polymerase chain reaction. Carbon or nitrogen availabilities were significantly influenced by clonal integration in the rhizosphere of shaded ramets. Clonal integration significantly increased extracellular enzyme activities and abundance of functional genes in the rhizosphere of shaded ramets. When rhizomes were connected, higher nitrogen turnover (nitrogen mineralization or nitrification rates) was exhibited in the rhizosphere of shaded offspring ramets. However, nitrogen turnover was significantly decreased by clonal integration in the rhizosphere of shaded mother ramets. Path analysis indicated that nitrogen turnover in the rhizosphere of shaded, offspring or mother ramets were primarily driven by the response of soil microorganisms to dissolved organic carbon or nitrogen. This unique in-situ experiment provided insights into the mechanism of nutrient recycling mediated by clonal integration. It was suggested that effects of clonal integration on the rhizosphere microbial processes were dependent on direction of photosynthates transport in clonal plant subjected to heterogeneous light conditions.

miR-338-3p inhibits epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma cells.

Down-regulation of the miRNA miR-338-3p correlates with the invasive ability of hepatocellular carcinoma (HCC) cells. However, it is currently unclear whether down-regulation of miR-338-3p induces epithelial-mesenchymal transition (EMT), which may be the underlying mechanism governing HCC invasion. Here, we demonstrate that restoration of miR-338-3p expression via transfection of a miR-338-3p mimic reversed EMT and inhibited the motility and invasiveness of HCC cells. Conversely, silencing of endogenous miR-338-3p expression with a miR-338-3p-specific inhibitor induced EMT and enhanced HCC cell motility. Additionally, Snail1 (an upstream regulatory protein of EMT) and Gli1 (a key transcription factor in the sonic hedgehog (SHH) signaling pathway) expression was up-regulated in cells treated with the miR-338-3p inhibitor and down-regulated by the miR-338-3p mimic. Further analyses demonstrated that miR-338-3p inhibitor-induced EMT in HCC cells was blocked by treatment with a small interfering RNA (siRNA) targeting Snail1, that the SHH signaling pathway was required for both miR-338-3p inhibitor-induced EMT and up-regulation of Snail1, and that miR-338-3p targeted a sequence within the 3'-untranslated region of N-cadherin mRNA. Notably, miR-338-3p expression was significantly down-regulated in HCC samples from patients with metastases and was associated with poor metastasis-free survival rates. Lastly, correlations between the expression levels of miR-338-3p and E-cadherin, Smoothened (SMO), Gli1, Snail1, N-cadherin, and vimentin were confirmed in HCC xenograft tumors and HCC patient specimens. Our findings suggest that miR-338-3p suppresses EMT and metastasis via both inhibition of the SHH/Gli1 pathway and direct binding of N-cadherin. miR-338-3p is a potential therapeutic target for metastatic HCC.

miR-601 is a prognostic marker and suppresses cell growth and invasion by targeting PTP4A1 in breast cancer.

MicroRNAs (miRNA) play important roles in the initiation and progression of breast cancer. Here, we investigated the role of miR-601 in breast cancer and found that its expression was significantly down-regulated in breast cancer tissues compared with matched adjacent non-cancerous breast tissues. Moreover, we found that down-regulation of miR-601 was closely associated with distant metastasis and poor distant metastasis-free survival in breast cancer. In addition, miR-601 levels were inversely correlated with metastatic potential of human breast cancer cell lines. Further experiments showed that ectopic overexpression of miR-601 suppressed breast cancer cell proliferation, migration and invasion, whereas miR-601 knockdown promoted breast cancer cell proliferation, migration and invasion. Furthermore, protein tyrosine phosphatase type IVA 1 (PTP4A1) was identified as a direct target of miR-601. Overexpression of miR-601 repressed PTP4A1 mRNA and protein expression. Conversely, inhibition of miR-601 increased PTP4A1 mRNA and protein expression. Taken together, our data suggest that miR-601 inhibits growth and invasion of breast cancer cells by targeting PTP4A1 and that miR-601 is a potential biomarker for prognosis and therapeutic target in breast cancer.