scholarly journals Autophagy activity in cholangiocarcinoma is associated with anatomical localization of the tumor

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253065
Author(s):  
Gábor Lendvai ◽  
Tímea Szekerczés ◽  
Ildikó Illyés ◽  
Milán Csengeri ◽  
Krisztina Schlachter ◽  
...  
Keyword(s):  
Cell Lines ◽  
Treatment Options ◽  
Tissue Microarrays ◽  
Molecular Characteristics ◽  
Prognostic Role ◽  
Poor Overall Survival ◽  
Ki 67 ◽  
Anatomical Localization ◽  
Autophagy Activity

The presence of autophagy has been indicated in cholangiocarcinoma (CC), which disease has poor prognosis and limited treatment options. Recently, CC has been classified by anatomical localization as intrahepatic (iCC), perihilar (pCC) and distal (dCC), showing different clinical and molecular characteristics. Thus, our aim was to compare autophagy activity in CC samples resected from different anatomical locations. Further, we investigated whether autophagy could be modulated in cell lines originated from iCC and extrahepatic CC (eCC) following the treatments with autophagy inhibitory and inducing agents. Tissue microarrays were prepared from 70 CC (28 iCC, 19 pCC and 23 dCC), 31 adjacent non-tumorous and 9 hepatocellular carcinoma (HCC) samples. Autophagy markers LC3, p62 and Beclin1 as well as proliferation marker Ki-67 were monitored by immunohistochemistry and were associated with patients’ survival. Modulation of autophagy was investigated in cell lines originated from iCC (HuH-28), eCC (TFK-1) and HCC (HepG2) by treating the cells with chloroquine (CQ) for inhibition and with Rapamycin, 5-Fluorouracil (5-FU) and Sorafenib for induction of autophagy. Our results indicated an inhibited autophagy in iCC and pCC tumor tissues, whereas active autophagy seemed to occur in dCC, especially in samples displaying low Ki-67 index. Additionally, low level of Beclin1 and high level of Ki-67 were associated with poor overall survival in dCC, suggesting the prognostic role of these proteins in dCC. Beside a baseline autophagy detected in each cell line, Rapamycin and 5-FU induced autophagy in iCC and HepG2 cell lines, Sorafenib in iCC cells. A chemotherapy agent in combination with CQ decreased IC50 effectively in the cell lines where basal and/or induced autophagy were present. In conclusion, we revealed differences in the autophagy activities of CC tissues and cell lines originated from different anatomical locations, which might influence patients’ treatment. Our results also suggest a prognostic role of Beclin1 and Ki-67 in dCC.

scholarly journals miR-1293 acts as a tumor promotor in lung adenocarcinoma via targeting phosphoglucomutase 5

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12140
Author(s):  
Bing Chen ◽  
Shiya Zheng ◽  
Feng Jiang
Keyword(s):  
Lung Adenocarcinoma ◽  
Cell Lines ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Ki 67 ◽  
Histologic Subtype ◽  
Tumor Promotor ◽  
Common Histologic Subtype ◽  
The Relationship

Background Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Studies have found that miR-1293 is related to the survival of LUAD patients. Unfortunately, its role in LUAD remains not fully clarified. Methods miR-1293 expression and its association with LUAD patients’ clinical characteristics were analyzed in TCGA database. Also, miR-1293 expression was detected in LUAD cell lines. Cell viability, migration, invasion and expression of MMP2 and MMP9 were measured in LUAD cells following transfection with miR-1293 mimic or antagomir. Phosphoglucomutase (PGM) 5 was identified to be negatively related to miR-1293 in LUAD patients in TCGA database, and their association was predicated by Targetscan software. Hence, we further verified the relationship between miR-1293 and PGM5. Additionally, the effect and mechanism of miR-1293 were validated in a xenograft mouse model. Results We found miR-1293 expression was elevated, but PGM5 was decreased, in LUAD patients and cell lines. Higher miR-1293 expression was positively related to LUAD patients’ pathologic stage and poor overall survival. miR-1293 mimic significantly promoted, whereas miR-1293 antagomir suppressed the viability, migration, invasion, and expression of MMP2 and MMP9 in LUAD cells. PGM5 was a target of miR-1293. Overexpression of PGM5 abrogated the effects of miR-1293 on the malignant phenotypes of LUAD cells. Administration of miR-1293 antagomir reduced tumor volume and staining of Ki-67 and MMP9, but elevated PGM5 expression in vivo. Conclusions miR-1293 promoted the proliferation, migration and invasion of LUAD cells via targeting PGM5, which indicated that miR-1293 might serve as a potential therapeutic target for LUAD patients.

scholarly journals Towards Personalization in the Curative Treatment of Gastric Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Astrid E. Slagter ◽  
Marieke A. Vollebergh ◽  
Edwin P. M. Jansen ◽  
Johanna W. van Sandick ◽  
Annemieke Cats ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Molecular Characteristics ◽  
Perioperative Chemotherapy ◽  
Current Standard ◽  
Common Cancer ◽  
Resectable Gastric Cancer

Gastric cancer is the fifth most common cancer worldwide and has a high mortality rate. In the last decades, treatment strategy has shifted from an exclusive surgical approach to a multidisciplinary strategy. Treatment options for patients with resectable gastric cancer as recommended by different worldwide guidelines, include perioperative chemotherapy, pre- or postoperative chemoradiotherapy and postoperative chemotherapy. Although gastric cancer is a heterogeneous disease with respect to patient-, tumor-, and molecular characteristics, the current standard of care is still according to a one-size-fits-all approach. In this review, we discuss the background of the different treatment strategies in resectable gastric cancer including the current standard, the specific role of radiotherapy, and describe the current areas of research and potential strategies for personalization of therapy.

scholarly journals Overhydroxylation of Lysine of Collagen Increases Uterine Fibroids Proliferation: Roles of Lysyl Hydroxylases, Lysyl Oxidases, and Matrix Metalloproteinases

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Marwa Kamel ◽  
Mohamed Wagih ◽  
Gokhan S. Kilic ◽  
Concepcion R. Diaz-Arrastia ◽  
Mohamed A. Baraka ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Treatment Options ◽  
Uterine Fibroids ◽  
Cross Linking ◽  
Ki 67 ◽  
Subsequent Formation ◽  
Lysyl Oxidases ◽  
Cross Links ◽  
Collagen Cross Linking

The role of the extracellular matrix (ECM) in uterine fibroids (UF) has recently been appreciated. Overhydroxylation of lysine residues and the subsequent formation of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) cross-links underlie the ECM stiffness and profoundly affect tumor progression. The aim of the current study was to investigate the relationship between ECM of UF, collagen and collagen cross-linking enzymes [lysyl hydroxylases (LH) and lysyl oxidases (LOX)], and the development and progression of UF. Our results indicated that hydroxyl lysine (Hyl) and HP cross-links are significantly higher in UF compared to the normal myometrial tissues accompanied by increased expression of LH (LH2b) and LOX. Also, increased resistance to matrix metalloproteinases (MMP) proteolytic degradation activity was observed. Furthermore, the extent of collagen cross-links was positively correlated with the expression of myofibroblast marker (α-SMA), growth-promoting markers (PCNA; pERK1/2;FAKpY397; Ki-67; and Cyclin D1), and the size of UF. In conclusion, our study defines the role of overhydroxylation of collagen and collagen cross-linking enzymes in modulating UF cell proliferation, differentiation, and resistance to MMP. These effects can establish microenvironment conducive for UF progression and thus represent potential target treatment options of UF.

scholarly journals Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4318
Author(s):  
Brittany P. Rickard ◽  
Christina Conrad ◽  
Aaron J. Sorrin ◽  
Mustafa Kemal Ruhi ◽  
Jocelyn C. Reader ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Biology ◽  
Metastatic Cancer ◽  
Treatment Options ◽  
Therapy Response ◽  
Therapy Resistance ◽  
Malignant Ascites ◽  
Molecular Characteristics ◽  
The Impact

Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of death from gynecologic malignancies. Despite decades of evidence showing that the accumulation of peritoneal fluid portends the poorest outcomes for cancer patients, the role of malignant ascites in promoting metastasis and therapy resistance remains poorly understood. This review summarizes the current understanding of malignant ascites, with a focus on ovarian cancer. The first section provides an overview of heterogeneity in ovarian cancer and the pathophysiology of malignant ascites. Next, analytical methods used to characterize the cellular and acellular components of malignant ascites, as well the role of these components in modulating cell biology, are discussed. The review then provides a perspective on the pressures and forces that tumors are subjected to in the presence of malignant ascites and the impact of physical stress on therapy resistance. Treatment options for malignant ascites, including surgical, pharmacological and photochemical interventions are then discussed to highlight challenges and opportunities at the interface of drug discovery, device development and physical sciences in oncology.

scholarly journals PROGNOSTIC ROLE OF KI - 67 INDEX AND MITOTIC INDEX IN NEUROENDOCRINE TUMORS OF HETEROGENOUS ORIGIN

2014 ◽  
Vol 3 (67) ◽  
pp. 14438-14444
Author(s):  
Triveni B ◽  
Sandeep Kumar ◽  
Sai Mallikarjun S ◽  
Lakshmi Sri
Keyword(s):  
Mitotic Index ◽  
Neuroendocrine Tumors ◽  
Prognostic Role ◽  
Ki 67

scholarly journals Death domain-associated protein (DAXX) expression is associated with poor survival in metastatic high-grade serous carcinoma

2020 ◽  
Vol 477 (6) ◽  
pp. 857-864
Author(s):  
Ben Davidson ◽  
Erin McFadden ◽  
Arild Holth ◽  
Marta Brunetti ◽  
Vivi Ann Flørenes
Keyword(s):  
Cell Lines ◽  
Western Blotting ◽  
Serous Carcinoma ◽  
High Grade ◽  
Death Domain ◽  
Poor Overall Survival ◽  
Clinical Role ◽  
Entire Cohort ◽  
Clinicopathologic Parameters

AbstractThe objective of this study was to analyze the expression and clinical role of mitosis regulators α-thalassemia/mental retardation syndrome X-linked (ATRX) and death-domain-associated protein (DAXX) in metastatic high-grade serous carcinoma (HGSC). ATRX and DAXX protein expression by immunohistochemistry was analyzed in 400 HGSC effusions. DAXX expression was additionally studied in 15 cancer cell lines, including 4 ovarian carcinoma lines, and in 81 of the 400 HGSC effusions using Western blotting. ATRX and DAXX were expressed in HGSC cells in 386/400 (96%) and 348/400 (87%) effusions, respectively. Western blotting showed DAXX expression in all 15 cell lines and in 70/81 (86%) HGSC effusions. DAXX expression by immunohistochemistry was higher in pleural compared to peritoneal effusions (p = 0.006) and in post-chemotherapy compared to pre-chemotherapy effusions (p = 0.004), and its expression was significantly associated with poor overall survival in univariate of the entire cohort (p = 0.014), as well as analysis limited to chemo-naïve effusions tapped at diagnosis (p = 0.038). The former association retained its prognostic role in Cox multivariate survival analysis (p = 0.011). ATRX expression was unrelated to clinicopathologic parameters or survival. In conclusion, DAXX is associated with disease progression and could be a prognostic marker in metastatic HGSC. Silencing this molecule may have therapeutic relevance in this cancer.

Interactions of Midostaurin (PKC412), Rapamycin and Ara-C in AML Cell Lines: Role of FLT3 Signalling.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2841-2841
Author(s):  
Claire H. Seedhouse ◽  
Shili Shang ◽  
Nigel Russell ◽  
Emma Das-Gupta
Keyword(s):  
Cell Lines ◽  
Low Dose ◽  
Treatment Options ◽  
Signalling Pathways ◽  
Wild Type ◽  
Treatment Regimens ◽  
Flt3 Inhibitor ◽  
In The Wild ◽  
Bv173 Cell

Abstract Treatment options for patients with AML who are unfit for intensive chemotherapy are currently very limited. Commonly used treatment regimens such as low dose Ara-C result in complete remission rates of 17% and these remissions are not sustained (Burnett et al 2007). There is a rationale to examine the effect of combining small molecule inhibitors of signalling pathways with low dose Ara-C with the aim to improve its antileukaemic activity. To this end we have studied the cytotoxic interactions of the FLT3 inhibitor PKC412 and the mTOR inhibitor rapamycin with Ara-C in isobologram analysis (CalcuSyn). 4 cell lines were studied: 2 with FLT3 ITDs (MV4-11 and MOLM13) and 2 wild type for FLT3 (HL-60 and BV173). As expected synergy was seen between Ara-C and PKC412 in the FLT3 ITD positive cell lines (CI50: 0.47 MOLM13 and 0.68 MV4-11), but not in the wild type cell lines where antagonism was noted (CI50: 1.21 BV173 and 1.7 HL-60). In contrast, the Ara-C and rapamycin combination was synergistic in all cell lines, irrespective of FLT3 status. When the combination of PKC412 and rapamycin was studied, high levels of synergy were observed in the FLT3 ITD cell lines (CI50: 0.16 MOLM13 and 0.26 MV4-11) and in the BV173 cell line (CI50: 0.37) which has been shown to have autocrine activation of wild type FLT3 (Zheng et al, 2004) but not in HL-60 cells, where the combination was antagonistic (CI50: 3.4). FLT3 signalling pathways converge with the mTOR pathway via AKT and therefore our results suggest that a double hit on FLT3 signalling is likely to be beneficial in the treatment of FLT3 positive leukemias. In contrast rapamycin augments the cytotoxicity of AraC independently of Flt3 status. The combination of all 3 drugs produced no further benefit compared to the use of Ara-C and rapamycin alone. These promising drug combinations warrant further investigation in clinical studies.

Flap Structure-Specific Endonuclease 1 (FEN1) May be a Key Mediator of Genome Instability in Myeloma: A Cellular Vulnerability with Potential Therapeutic Significance

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4440-4440
Author(s):  
Masood A Shammas ◽  
Leutz Buon ◽  
Subodh Kumar ◽  
Mehmet K. Samur ◽  
David Alagpulinsa ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Genetic Recombination ◽  
Nuclease Activity ◽  
Gene Signature ◽  
Genomic Integrity ◽  
Dna Breaks ◽  
Poor Overall Survival

Abstract Multiple myeloma is associated with a marked genomic instability which leads to acquisition of mutational changes, some of which underlie disease progression including development of drug resistance and poor clinical outcome. Understanding mechanisms of genomic instability is, therefore, extremely important to develop novel improved therapeutic strategies. Since dysregulated nuclease activity can induce DNA breaks and genetic recombination eventually disrupting genomic integrity, we have evaluated nuclease activity and specific nucleases for their role in genomic instability in MM. We previously identified a nuclease gene signature correlating with genomic instability in a myeloma patient dataset and tested it for correlation with survival in two other datasets. We showed that expression of these genes associated with poor overall as well as event free survival in both datasets, IFM172 (P< 0.00005) and gse24080 (P< 0.0008). We have now further refined this signature to a nine gene signature and tested it for correlation with survival in three different MM patient datasets in which gene expression was evaluated either by microarray (GSE39754, n=170; gse24080; n=559) or RNASeq (n=300). Elevated expression of nine gene signature significantly correlated with poor overall survival in all three datasets (P ≤ 1e-06 for IFM70 and gse24080 and P = 0.002 for RNASeq). To biologically and molecularly validate this signature, we conducted an shRNA screen and evaluated impact of all nine genes in signature as well as four additional nucleases on homologous recombination (HR) activity, using a plasmid based assay in which HR produces a functional luciferase gene. Of thirteen nucleases tested, knockdown of seven was associated with ≥50% inhibition of HR activity; the strongest (~80%) inhibition of HR activity was observed by FEN1 knockdown. To further investigate FEN1, we confirmed the role of this nuclease in HR using a different (DRGFP) assay in which homology-based recombination between two mutated genes, generates a functional GFP gene. Using this assay, we showed that FEN1-knockdown in U2OS cells was also associated with a strong (71%) inhibition of HR activity, confirming the role of this nuclease in dysregulation of HR. Evaluation by Western blotting in three different normal PBMC samples and eleven MM cell lines showed that FEN1 was not detected in normal cells, whereas highly expressed in MM cells. Expression profile using microarray also showed that FEN1 is elevated in a subset of MM patient samples. Knockdown of FEN1 in two MM cell lines, RPMI and H929, led to reduction in overall nuclease activity (by ~40%) as assessed by a fluorescence based nuclease activity assay and a similar (~50%) reduction in the levels of gamma-H2AX, a marker of DNA breaks. These data indicate that FEN1 nuclease activity contributes to increased DNA breaks as well as elevated HR activity in MM cells. To further understand the role of FEN1 in dysregulated HR and genome stability in MM, using mass spectrometry, we have identified the interacting proteins. Role of FEN1 in acquisition of new genomic changes over time in MM cells is cuurently being investigated in our laboratory. In summary, we show that FEN1 is an important component of machinery maintaining genomic integrity and plays a significant role in genome dysregulation in myeloma. The FEN1 dysfunction may provide a cellular vulnerability that can be therapeutically exploited. Disclosures No relevant conflicts of interest to declare.

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