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Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related death. High recurrence rates after curative resection and the lack of specific biomarkers for intrahepatic metastases are major clinical problems. Recently, exosomal microRNAs (miRNAs) have been reported to have a role in the formation of the pre‐metastatic niche and as promising biomarkers in patients with malignancy. Here we aimed to clarify the molecular mechanisms of intrahepatic metastasis and to identify a novel biomarker miRNA in patients with HCC. A highly intrahepatic metastatic cell line (HuH‐7M) was established by in vivo selection. HuH‐7M showed increased proliferative ability and suppression of apoptosis and anoikis. HuH‐7M and the parental cell (HuH‐7P) showed the similar expression of epithelial‐mesenchymal transition markers and cancer stem cell markers. In vivo, mice treated with exosomes derived from HuH‐7M showed increased tumorigenesis of liver metastases. Exosomes from HuH‐7M downregulated endothelial cell expression of vascular endothelial‐cadherin (VE‐cadherin) and zonula occludens‐1 (ZO‐1) in non‐cancerous regions of liver and increased the permeability of FITC‐dextran through the monolayer of endothelial cells. The miRNAs (miR‐638, miR‐663a, miR‐3648, and miR‐4258) could attenuate endothelial junction integrity by inhibiting VE‐cadherin and ZO‐1 expression. In patients with HCC, higher serum exosomal miR‐638 expression was associated with tumor recurrence. In conclusion, the miRNAs secreted from a highly metastatic cancer cell can promote vascular permeability via downregulation of endothelial expression of VE‐cadherin and ZO‐1. Serum exosomal miR‐638 expression holds potential for serving as a significant and independent prognostic marker in HCC. miR‐638, miR‐663a, miR‐3648, and miR‐4258 downregulate VE‐cadherin and ZO‐1 expression in HUVECs.

The cancer drug gemcitabine (GEM) is a key drug for treating pancreatic ductal adenocarcinoma (PDAC), but PDAC cells develop chemoresistance after long-term administration. Since the tolerance was immediately spread to every PDAC tissue in a patient, it is assumed that some certain efficient mechanisms underlay in the development of chemoresistance. Changes in the levels of particular microRNAs or alterations in intercellular communication play a dominant role in chemoresistance development, and recent data also suggest that exosomes play an important role in this process. In this study, we revealed that the loop conferred chemoresistance in PDAC cells. The loop was as follows; 1, The long-term exposure of GEM increased miR-155 expression in PDAC cells. 2, The increase of miR-155 induced two different functions; exosome secretion and chemoresistance ability via facilitating the anti-apoptotic activity. 3, Exosome deliver the miR-155 into the other PDAC cells and induce the following function. The target therapy to miR-155 or the exosome secretion effectively attenuated the chemoresistance, and these results were validated with both clinical samples and in vivo experiments. This mechanism represents a novel therapeutic target in GEM treatment to PDAC.

BackgroundA procedure-based laparoscopic liver resection (LLR) classification (IMM classification) stratified 11 different LLR procedures into 3 grades. IMM classification assessed the difficulty of LLR differently than an index-based LLR classification (IWATE criteria), which scored each procedure on an index scale of 12. We validated the difference of 3 IMM grades using an external cohort, evaluated the IMM classification using the scores of the IWATE criteria, and compared the performance of IMM classification with the IWATE criteria and the minor/major classification.MethodsPatients undergoing LLR without simultaneous procedures were selected from a prospectively maintained database at the Institut Mutualiste Montsouris (IMM cohort) and from the database of 43 Japanese institutions (JMI cohort). Surgical and postoperative outcomes were evaluated according to the 3 IMM grades using the JMI cohort. The 11 LLR procedures included in the IMM classification were scored according to the IWATE criteria. The area under the curves (AUCs) for surgical and postoperative outcomes were compared.ResultsIn the JMI (n = 1867) cohort, operative time, blood loss, conversion rate, and major complication rate were significantly associated with a stepwise increase in grades from I to III (all, P < 0.001). In the IMM (n = 433) and JMI cohorts, IMM grades I, II, and III corresponded to three low-scoring, two intermediate-scoring, and six high-scoring LLR procedures as per the IWATE criteria, respectively. Mean ± standard deviation among the IMM grades were significantly different: 3.7 ± 1.4 (grade I) versus 7.5 ± 1.7 (grade II) versus 10.2 ± 1.0 (grade III) (P < 0.001) in the IMM cohort and 3.6 ± 1.4 (grade I) versus 6.7 ± 1.5 (grade II) versus 9.3 ± 1.4 (grade III) (P < 0.001) in the JMI cohort. The AUCs for surgical and postoperative outcomes are higher for the 3-level IMM classification than for the minor/major classification.ConclusionsThe difference of 3 IMM grades with respect to surgical and postoperative outcomes was validated using an external cohort. The 3-level procedure-based IMM classification was in accordance with the index-based IWATE criteria. The IMM classification performed better than the minor/major classification for stratifying LLR procedures.

BackgroundCD36, a multi-ligand scavenger receptor, has been associated with several cancers. Many studies have revealed that CD36 contributed to cancer malignancy. This study aimed to reveal the function of CD36 expression in pancreatic ductal adenocarcinoma (PDAC).MethodsCD36 expression was characterized using immunohistochemistry in 95 clinical specimens resected from patients with PDAC. We divided patients into two groups, with different CD36 expression levels, and analyzed and compared their prognoses. CD36 expression was also assessed in PDAC cell lines. Gemcitabine-resistant (GR) PDAC cell lines were transfected with small interfering RNA (siRNA) that specifically targeted CD36 to evaluate chemoresistance and apoptosis.ResultsIn resected PDAC samples, CD36 expression was significantly correlated with microinvasion into the venous system (p = 0.0284). Patients with high CD36 expression had significantly lower overall survival (OS) and recurrence-free survival (RFS) rates than patients with low expression; thus, CD36 was an independent prognostic factor for OS and RFS. In subgroup analyses, CD36 was an independent risk factor for OS and RFS in 59 patients treated with gemcitabine adjuvant chemotherapy. CD36 expression was upregulated in PDAC–GR cell lines compared with the PDAC parent cell line. Transduction with siRNA downregulated CD36, which reduced PDAC cell resistance to gemcitabine and inhibited anti-apoptosis proteins.ConclusionCD36 expression influenced gemcitabine resistance by regulating anti-apoptosis proteins. High CD36 expression was a significant, unfavorable prognostic factor in PDAC. Anti-CD36 treatment might serve as an optional treatment for lowering resistance to gemcitabine.

PurposeIn this study, we aim to clarify whether exosomes secreted from hepatocellular carcinoma (HCC) cells under hypoxia affect angiogenesis in endothelial cells.MethodsExosomes derived from human liver cancer cell lines were cultured under hypoxic or normoxic conditions for 24 h, isolated using ExoQuick-TC®, and co-cultured with HUVECs to evaluate angiogenic activity. We also evaluated the expression of miR-155 in the exosomes from 40 patients with HCC.ResultsExosomes under hypoxia remarkably enhanced tube formation of HUVECs. Both cellular and exosomal miR-155 were significantly up-regulated under hypoxic conditions. Knockdown of miR-155 in HCC cells attenuated the promotion of tube formation by exosomes under hypoxia in HUVECs, and high expression of exosomal miR-155 in preoperative plasma was significantly correlated with early recurrence.ConclusionThese results suggest that exosomes derived from HCC cells under hypoxia induce tube formation of HUVECs and that exosomal miR-155 may affect angiogenic activity in HCC.

Centrosomes are highly conserved organelles that act as the major microtubule-organizing center (MTOC) in animal somatic cells. Through their MTOC activity, centrosomes play various roles throughout the cell cycle, such as supporting cell migration in interphase and spindle organization and positioning in mitosis. Various approaches for removing centrosomes from somatic cells have been developed and applied over the past few decades to understand the precise roles of centrosomes. Centrinone, a reversible and selective PLK4 (polo-like kinase 4) inhibitor, has recently emerged as an efficient approach to eliminate centrosomes. In this review, we describe the latest findings on centrosome function that have been revealed using various centrosome-eliminating approaches. In addition, we discuss our recent findings on the mechanism of centrosome-independent spindle bipolarization, discovered through the use of centrinone.Key words: centrosome, centrinone, mitotic spindle, bipolarity, NuMA

The triplet microtubule, a core structure of centrioles crucial for the organization of centrosomes, cilia, and flagella, consists of unclosed incomplete microtubules. The mechanisms of its assembly represent a fundamental open question in biology. Here, we discover that the ciliopathy protein HYLS1 and the β-tubulin isotype TUBB promote centriole triplet microtubule assembly. HYLS1 or a C-terminal tail truncated version of TUBB generates tubulin-based superstructures composed of centriole-like incomplete microtubule chains when overexpressed in human cells. AlphaFold-based structural models and mutagenesis analyses further suggest that the ciliopathy-related residue D211 of HYLS1 physically traps the wobbling C-terminal tail of TUBB, thereby suppressing its inhibitory role in the initiation of the incomplete microtubule assembly. Overall, our findings provide molecular insights into the biogenesis of atypical microtubule architectures conserved for over a billion years. Centrioles are characterized by an atypical triplet microtubule structure. Here, the authors discover that the ciliopathy protein HYLS1 promotes the assembly of triplet microtubules within human centrioles.

Background/AimWe previously demonstrated that inflammatory cytokine interleukin-6 (IL-6) was produced during cancer progression, worked together with transforming growth factor-beta 1 (TGF-β1), and induced the epithelial–mesenchymal transition (EMT) with chemo-resistance against gemcitabine (GR) at the invasion front of biliary tract cancers (BTCs). However, the significance of cytokine-induced T cell accumulation at the tumor microenvironment in biliary tract cancer (BTC) is not well understood. Because these cytokines (IL-6 and TGF-β1) are able to differentiate naïve T cells into Foxp3-expressing T cells (Tregs) and/or IL-17–producing T helper 17 (Th17) cells, we investigated the relationship between heterogeneous, cancer-producing cytokines and T cell differentiation.MethodsIn total, 127 curative resected specimens from patients with BTCs at Osaka University Hospital between 2000 and 2012 were evaluated for IL-6, TGF-β1, Tregs, and Th17 cells by immunohistochemistry. The ability of BTC–GR cells to undergo T cell differentiation was investigated in vitro.ResultsTregs accumulated at the tumor center and Th17 cells accumulated at the invasion front during cancer progression and/or metastasis; each signaled poor prognosis. Treg accumulation was related to TGF-β1 expression by cancer cells, and Th17 cell accumulation was related to IL-6 expression by cancer cells, in resected specimens; this was confirmed in vitro. Compared with parent cells, GR cells produced IL-6 but not TGF-β1 in a time-dependent manner, had EMT features, and induced T cell differentiation to Th17 cells but not Tregs.ConclusionCytokines produced by cancer cells (IL-6 and TGF-β1) induced heterogeneity of Tregs and Th17 cells in the tumor microenvironment, supporting progression of BTC.

Current therapies for pancreatic ductal cancer (PDAC) do not sufficiently control distant metastasis. Thus, new therapeutic targets are urgently needed. Numerous studies have suggested that the epithelial‐mesenchymal transition (EMT) is pivotal for metastasis of carcinomas. The fact that the EMT is reversible suggests the possibility that it is induced by an epigenetic mechanism. In this study, we aimed to investigate the role of histone deacetylase 1 (HDAC1), which is an epigenetic mechanism on distant metastasis of PDAC. We investigated the HDAC1 expression in 103 resected PDAC specimens obtained from patients who were treated with/without preoperative therapy using immunohistochemistry. To validate the findings in the clinical samples, we evaluated the HDAC1 activity, the EMT‐associated genes and the migration/invasion ability in vitro, and performed an HDAC1 inhibitor assay. The high expression of HDAC1 in clinical samples was significantly associated with poor progression‐free survival, especially distant metastasis‐free survival. In vitro, HDAC1 inhibitors decreased the invasion ability and reversed the EMT change; the only factor to show a concomitant decrease was the expression of SNAIL. We confirmed that the HDAC1 expression was associated with the SNAIL expression in clinical samples. Moreover, the resistant cells and parental cells did not show any significant differences in the expression of HDAC1; this was consistent with the finding that preoperative therapy did not alter the HDAC1 expression in clinical samples. The targeting of HDAC1, which could suppress metastasis by inhibiting the EMT, is a promising treatment option for PDAC. The expression of histone deacetylase 1 (HDAC1) in pancreatic ductal carcinoma (PDAC) indicates a higher migration ability, and a lack of response to chemotherapy/radiotherapy. Therapy targeting HDAC1, which might suppress metastasis, would be a promising treatment option for PDAC.

Background Fatty pancreas (FP) was recently recognized as a risk factor for pancreatic ductal adenocarcinoma (PDAC). It is unclear whether computed tomography (CT) can be used to make a FP diagnosis. This study investigated whether CT could provide a predictive value for PDAC by diagnosing FP. Methods The study included 183 consecutive patients who underwent distal pancreatectomy from February 2007 to January 2017, including 75 cases of PDAC and 108 cases of other pancreatic disease. Pancreatic CT density (pancreatic index; PI) at the initial diagnosis was calculated by dividing the CT number in the pancreas by the number in the spleen. To assess whether CT could be used to detect FP, 43 cases were evaluated pathologically for FP. We investigated the correlation between FP and PI, and determined the optimal PI cutoff value for detecting FP using receiver operating characteristics analysis. We then investigated whether the PI value could be used as a predictor for PDAC. Results Fourteen cases (32.6%) were pathologically diagnosed with FP. PI was significantly lower in the FP group versus the non-FP group (0.51 vs. 0.83; p  = 0.0049). ROC analysis indicated that the PI had good diagnostic accuracy for FP diagnosis (cutoff value 0.70; sensitivity 0.79, specificity 0.79). Low PI (≤0.70) was identified in the multivariate analysis as an independent risk factor for PDAC (odds ratio 2.31; p  = 0.023). Conclusions PI was strongly associated with pathological FP, which was independently associated with PDAC. PI shows promise as an imaging predictor for PDAC.