We examined gene expression of hepatocyte growth factor (HGF) and HGF receptor (HGFR), or product of proto-oncogene c-met (c-met), in smokers and nonsmokers with adenocarcinoma (ADC) by suppression ...subtractive hybridization and microarray techniques. Expression of HGF and c-met was confirmed by RT-PCR. HGF content in the respective tumor mass and nontumor lung tissue was measured by ELISA. HGF in pathologic samples was localized by immunohistochemistry and in situ hybridization. Our results indicate that overexpression of HGFR was frequently detected in ADC cells, whereas overexpression of HGF was detected in alveolar type II (ATII) cells. Overexpression of HGF was correlated with cigarette smoking and tumor stages. In vitro, HGF expression was evaluated in isolated murine ATII cells and in 12 ADC cell lines, and we found that nicotine activated HGF expression in ATII cells and lung cancer cells.
•p-Cresol (PC), a uremic toxin, decreases proliferation of renal proximal tubular cells (RPTC).•PC induces autophagy in RPTC through c-Jun activation mediated p62 accumulation.•PC promotes autophagic ...cell death in RPTC via caspase 8, followed by caspase 3 activation, which participates significantly to cell apoptosis.
Higher serum level of p-cresol (PC) in chronic kidney disease (CKD) patients has been linked with CKD progression. The toxic effect of PC on diverse cells has been reported by prior studies, except for renal tubular cells. Both autophagy and apoptosis contribute to renal tubular cell death, yet evidence of its response to PC is limited and their crosstalk is still unclear. Autophagy is an important cellular process involved in toxin-induced cell death. Renal tubular cell death in tubular injury is thought to be one of the key events causing the progression of CKD. Thus, we treated rat (NRK-52E) and human (HRPTEC) renal proximal tubular cells (RPTC) with PC and found the cell proliferation was significantly decreased. Cell apoptosis was significantly increased and accompanied with the activation of autophagy as evidenced by increases in LC3-II, beclin 1 and Atg 4. We also found an increase of p62 by c-Jun activation. p62 accumulation could mediate the activation of caspase 8-dependent cell apoptosis. Conversely, knockdown of p62 by siRNA of p62 had the opposite effect by arresting LC3-II accumulation and promoting increasing cell viability. We conclude that PC triggered autophagic RPTC death via JNK-mediated p62 accumulation and then activated caspase 8-dependent cell death pathway. PC can be considered as one of the key events causing progression of CKD, which might affect drug disposition in CKD cases.
Dear Editor, I am Dr Tzu-Chun Lin, from the Department of Dermatology, China Medical University Hospital, Taichung, Taiwan, China. We write to you to present a rare case of plexiform variant of ...schwannoma on the glans penis.
To determine the association of human papillomavirus (HPV) infection with the expression of dihydrodiol dehydrogenase (DDH) in uterine cervical cancer (UCC).
In situ hybridization (ISH) and ...immunohistochemistry were applied to examine pathological specimens of 145 patients with UCC.
By ISH, HPV16/18 DNA was detected in 108 (74.5%) UCC cases. DDH expression determined by immunohistochemistry was detected in 81 (75%) lesions among 108 HPV-positive cases. In contrast, of 37 HPV-negative cases, DDH was only detected in 16 (43.2%) of the lesions. A significant correlation was found between DDH expression and the presence of HPV (
P < 0.001), FIGO stage (
P = 0.004), lymph node involvement (
P < 0.001), as well as patients' survival (
P = 0.002). In vitro, DDH expression was also found closely associated with HPV infection, and DDH content was proportional to cell sensitivity for cisplatin and doxorubicin.
HPV infection provokes local inflammation, which can then induce DDH expression and drug resistance in UCC. The detailed biological relationship among HPV infection, expression of DDH and drug resistance, however, remains to be clarified.
ATPase-family, AAA domain containing 3A (ATAD3A) is located on human chromosome 1p36.33, and high endogenous expression may associate with radio- and chemosensitivity. This study was conducted to ...investigate the significance of ATAD3A in glioblastoma multiforme (GBM).
Clinical significance of ATAD3A expression was assessed by immunohistochemistry in 67 GBM specimens, and prognostic value was assessed in 32 GBM patients statistically. To investigate in vitro phenotypic effects of ATAD3A, cell viability was measured using a clonogenic survival assay under either knockdown or ectopic expression of ATAD3A in GBM cell lines. The effects of ATAD3A knockdown on targeted DNA repair-associated proteins in T98G cells were evaluated using immunofluorescence and Western blotting.
Clinically, high expression of ATAD3A was independent of O(6)-DNA methylguanine-methyltransferase methylation status and correlated with worse prognosis. In vitro, high ATAD3A-expressing T98G cells were more resistant to radiation-induced cell death compared with control and low endogenous ATAD3A U87MG cells. After silencing ATAD3A, T98G cells became more sensitive to radiation. On the other hand, enforced ATAD3A expression in U87MG cells exhibited increased radioresistance. ATAD3A may coordinate with aldo-keto reductase genes and participate in bioactivation or detoxication of temozolomide. Surprisingly, deficient DNA repair after irradiation was observed in T98G/ATAD3A knockdown as a result of decreased nuclear ataxia telangiectasia mutated kinase and histones H2AX and H3, which was also evidenced by the sustained elevation of poly (ADP-ribose) polymerase prior to and after radiation treatment.
Our data suggest that high expression of ATAD3A is an independent biomarker for radioresistance in GBM. ATAD3A could be a potential target for therapy.
Abstract Cutaneous clear cell sarcoma (CCS) is a rare soft tissue malignancy that typically manifests in the distal extremities of young adults. Although it shows melanocytic differentiation, CCS is ...clearly pathologically and genetically distinct from malignant melanoma. Here, we report the case of a 43-year-old male who had an asymptomatic, deep-seated, slowly enlarging, firm mass over the right heel for 30 years that recently and rapidly progressed with tenderness. We arranged for the total excision of the tumor. Pathological and cytogenetic analysis of the biopsied specimen showed that it was a clear cell sarcoma. Computed tomography and positron emission tomography scans showed no signs of metastasis, and no other abnormal hypermetabolic lesions were detected. Wide excision with split-thickness skin graft and a sentinel lymph node biopsy were performed. Because of positive findings in the sentinel lymph nodes, the patient was transferred to the plastic surgery department for further radical popliteal and inguinal lymph node dissection. The patient has received regular outpatient follow-up care in our hospital for the past 8 months with no evidence of recurrence.
In eukaryotic cells, transport of the newly synthesized proteins and phospholipids to the appropriate subcellular target compartments is essential for maintaining organelle morphology and cell ...survival. In animal cells, mitochondria are major organelles containing DNA genome that encodes only for a small fraction of their proteins, which are required for the organelle function. Most mitochondrial proteins are encoded by the nuclear genes and imported to the mitochondria following protein synthesis. Apoptosis-inducing factor (AIF), an essential FAD-dependent NADH oxidase for the oxidative phosphorylation, is located in the intermembranous space and contains mitochondrial localization signals. However, the import mechanism of AIF to the mitochondria is not yet studied. Using sucrose gradient ultracentrifugation and immunoblotting, AIF was detected in fractions of the endoplasmic reticulum, mitochondria-associated membranes (MAM) and mitochondria, and AIF from these fractions was resistant to trypsin in the absence of digitonin, suggesting that AIF could be protected by phospholipids. Knockdown of dynamin-related protein 1 (DRP1kd) expression reduced AIF levels in the mitochondria, but increased AIF concentrations in the MAM. Knockdown of mitofusin-2 (Mfn-2kd) or ATPase family AAA domain containing 3A (ATAD3Akd) expression, however, reduced AIF levels in the mitochondria and increased the number of transport vesicles that contained AIF in the cytosol, indicating that ATAD3A and Mfn-2 were respectively essential for the import and fusion of transport vesicles into the mitochondria. Here we show that AIF is imported from the endoplasmic reticulum to the mitochondria via mitochondria-associated membranes and transport vesicles.
Abstract Objective Vulvar cancer is rare in Eastern females, especially in pre- and peripubertal girls. The prognosis of vulvar cancer is poor and treatment is variable. Case Report A 14-year-old ...girl suffered from a left vulvar tenderness mass and underwent excision of the mass. The diagnosis of the pathology was vulvar yolk tumor with an embryonal carcinoma. After the vulvectomy, inguinal area lymph node dissection, chemotherapy (bleomycin, etoposide and cisplatin) treatment and radiotherapy, metastasis to lung was also noted after eight months. Resection of lung tumor was performed. She received chemotherapy with a combination of paclitaxel, ifosphamide and cisplatin (TIP) and received peripheral blood stem cell transplantation (PBSCT) twice and chemotherapy treatment of gemitabine and oxaliplatin (GEMOX). Up until now, the patient has been free of disease. Conclusion High-dose TIP and GEMOX chemotherapy plus PBSCT for bone marrow rescues could be considered to treat patients with metastatic malignant vulvar germ cell tumor after failed first-line chemotherapy and radiation.
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