RESUMEN
Cholangiocarcinoma (CCA) is resistant to systemic chemotherapies that kill malignant cells mainly through DNA damage responses (DDRs). Recent studies suggest that the involvement of 2-oxoglutarate (2-OG) dependent dioxygenases in DDRs may be associated with chemoresistance in malignancy, but how 2-OG impacts DDRs in CCA chemotherapy remains elusive. We examined serum 2-OG levels in CCA patients before receiving chemotherapy. CCA patients are classified as progressive disease (PD), partial response (PR), and stable disease (SD) after receiving chemotherapy. CCA patients classified as PD showed significantly higher serum 2-OG levels than those defined as SD and PR. Treating CCA cells with 2-OG reduced DDRs. Overexpression of full-length aspartate beta-hydroxylase (ASPH) could mimic the effects of 2-OG on DDRs, suggesting the important role of ASPH in chemoresistance. Indeed, the knockdown of ASPH improved chemotherapy in CCA cells. Targeting ASPH with a specific small molecule inhibitor also enhanced the effects of chemotherapy. Mechanistically, ASPH modulates DDRs by affecting ATM and ATR, two of the major regulators finely controlling DDRs. More importantly, targeting ASPH improved the therapeutic potential of chemotherapy in two preclinical CCA models. Our data suggested the impacts of elevated 2-OG and ASPH on chemoresistance through antagonizing DDRs. Targeting ASPH may enhance DDRs, improving chemotherapy in CCA patients.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Ácido Aspártico/metabolismo , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Daño del ADN , Ácidos Cetoglutáricos , Oxigenasas de Función Mixta/genéticaRESUMEN
OBJECTIVE: To determine if SARS-CoV-2, which has led to the rapidly spreading COVID-19 global pandemic, is sexually transmitted. Since the putative receptor for the virus is identified in reproductive organs, it is also important to examine if COVID-19 may affect human fertility. EVIDENCE REVIEW: A systematic review of English publications was conducted up to December 11, 2020 in PubMed, NIH iCite COVID-19 portfolio, Cochrane Library, and Google Scholar databases, searching for SARS-CoV-2 in the testes; seminal, prostatic, and vaginal fluids; and cervical smears. A total of 1,997 records were identified, duplicates were removed, and 1,490 records were reviewed for eligibility by examining titles and abstracts. Subsequently, 202 full-text relevant articles were reviewed by 2 independent reviewers. Forty-seven studies (literature reviews, editorials, and guidelines) were assessed qualitatively, and 23 studies that tested the male and female reproductive tracts of patients with COVID-19 for SARS-CoV-2 were quantitatively analyzed. RESULTS: No epidemiological investigations to date have described evidence suggesting that COVID-19 is an STD. While angiotensin-converting enzyme 2 receptor is found in the reproductive organs, the lack of co-expression of the TMPRSS2 modulatory protein, required for SARS-CoV-2 cell entry, in testicular cells, sperm, or oocytes, argues against the hypothesis that gametes transmit SARS-CoV-2. Molecular detection studies of SARS-CoV-2 RNA in the male and female reproductive tracts were summarized: 98.0% (293/299) of the seminal fluids, 16/17 testicular biopsies, all 89 prostatic fluids, 98.3% (57/58) of the vaginal fluids, all 35 cervical smears, and all 16 oocyte samples tested negative for SARS-CoV-2. None of the studies confirmed sexual transmission of SARS-CoV-2. Nonetheless, COVID-19 may have detrimental effects on male reproduction by inducing orchitis and/or decreasing testosterone levels, sperm counts, and motility. CONCLUSION: On the basis of the current worldwide published information, COVID-19 is not an STD. This information is important for clinicians, proposed guidelines for public health, U.S. Food and Drug Administration guidelines for gamete and tissue donor eligibility, and fertility treatments. Universal precautions, currently practiced worldwide, are adequate and sufficient at this time to prevent the transmission of known or unknown viral infections. We suggest that recovered patients of COVID-19, especially those with infertility, should be evaluated for their ovarian and testicular function.
RESUMEN
BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a highly lethal disease without effective therapeutic approaches. The whole-genome sequencing data indicate that about 20% of patients with CCA have isocitrate dehydrogenase 1 (IDH1) mutations, which have been suggested to target 2-oxoglutarate (OG)-dependent dioxygenases in promoting CCA carcinogenesis. However, the clinical study indicates that patients with CCA and mutant IDH1 have better prognosis than those with wild-type IDH1, further complicating the roles of 2-OG-dependent enzymes. APPROACH AND RESULTS: This study aimed to clarify if ten-eleven translocation 1 (TET1), which is one of the 2-OG-dependent enzymes functioning in regulating 5-hydroxymethylcytosine (5hmC) formation, is involved in CCA progression. By analyzing The Cancer Genome Atlas (TCGA) data set, TET1 mRNA was found to be substantially up-regulated in patients with CCA when compared with noncancerous bile ducts. Additionally, TET1 protein expression was significantly elevated in human CCA tumors. CCA cells were challenged with α-ketoglutarate (α-KG) and dimethyl-α-KG (DM-α-KG), which are cosubstrates for TET1 dioxygenase. The treatments with α-KG and DM-α-KG promoted 5hmC formation and malignancy of CCA cells. Molecular and pharmacological approaches were used to inhibit TET1 activity, and these treatments substantially suppressed 5hmC and CCA carcinogenesis. Mechanistically, it was found that knockdown of TET1 may suppress CCA progression by targeting cell growth and apoptosis through epigenetic regulation. Consistently, targeting TET1 significantly inhibited CCA malignant progression in a liver orthotopic xenograft model by targeting cell growth and apoptosis. CONCLUSIONS: Our data suggest that expression of TET1 is highly associated with CCA carcinogenesis. It will be important to evaluate TET1 expression in CCA tumors before application of the IDH1 mutation inhibitor because the inhibitor suppresses 2-hydroxyglutarate expression, which may result in activation of TET, potentially leading to CCA malignancy.