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Cancer Med ; 9(3): 988-998, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31846222


OBJECTIVE: Stage I-II uterine papillary serous carcinoma (UPSC) has aggressive biological behavior and leads to poor prognosis. However, clinicopathologic risk factors to predict cancer-specific survival of patients with stage I-II UPSC were still unclear. This study was undertaken to develop a prediction model of survival in patients with early-stage UPSC. METHODS: Using Surveillance, Epidemiology, and End Results (SEER) database, 964 patients were identified with International Federation of Gynecology and Obstetrics (FIGO) stage I-II UPSC who underwent at least hysterectomy between 2004 and 2015. By considering competing risk events for survival outcomes, we used proportional subdistribution hazards regression to compare cancer-specific death (CSD) for all patients. Based on the results of univariate and multivariate analysis, the variables were selected to construct a predictive model; and the prediction results of the model were visualized using a nomogram to predict the cancer-specific survival and the response to adjuvant chemotherapy and radiotherapy of stage I-II UPSC patients. RESULTS: The median age of the cohort was 67 years. One hundred and sixty five patients (17.1%) died of UPSC (CSD), while 8.6% of the patients died from other causes (non-CSD). On multivariate analysis, age ≥ 67 (HR = 1.45, P = .021), tumor size ≥ 2 cm (HR = 1.81, P = .014) and >10 regional nodes removed (HR = 0.52, P = .002) were significantly associated with cumulative incidence of CSD. In the age ≥67 cohort, FIGO stage IB-II was a risk factor for CSD (HR = 1.83, P = .036), and >10 lymph nodes removed was a protective factor (HR = 0.50, P = .01). Both adjuvant chemotherapy combined with radiotherapy and adjuvant chemotherapy alone decreased CSD of patients with stage I-II UPSC older than 67 years (HR = 0.47, P = .022; HR = 0.52, P = .024, respectively). The prediction model had great risk stratification ability as the high-risk group had higher cumulative incidence of CSD than the low-risk group (P < .001). In the high-risk group, patients with post-operative adjuvant chemoradiotherapy had improved CSD compared with patients who did not receive radiotherapy nor chemotherapy (P = .037). However, there was no such benefit in the low-risk group. CONCLUSION: Our prediction model of CSD based on proportional subdistribution hazards regression showed a good performance in predicting the cancer-specific survival of early-stage UPSC patients and contributed to guide clinical treatment decision, helping oncologists and patients with early-stage UPSC to decide whether to choose adjuvant therapy or not.

Front Oncol ; 9: 1086, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31750234


Background: Chemotherapy is an essential component for comprehensive cancer treatment, while drug resistance usually fails therapy. DNA repair mechanism of cancer cells restrains the efficacy of therapeutics targeting DNA damage. Investigating target-inducing irreversible cell death of cancer cells may be promising. Methods: The present study used lung cancer cell lines, transplanted tumor model of lung cancers derived from patients with lung adenocarcinoma, and molecular experiments to investigate the effects and mechanism of Actinomycin D (Act D)-activated RNase L in lung canceers. Results: We report that RNase L, when activated by Act D, induces Caspase-3/PARP activation. The latter further enables ROCK-1 to initiate subsequent membrane blebbing and, meanwhile, result in DNA cleavage and cell cycle arrest mediated by H2A.X/H2B-p21 axis, leading to irreversible DNA damage, and apoptosis of lung cancer cells. The present study highlighted the crucial role of RNase L in triggering apoptosis mechanism through the Caspase-3/ROCK-1/PARP/H2A.X+H2B/p21 axis during Act D treatment. Moreover, activation of RNase L suppressed the tumor formation and the induction of lung cancer stem cells. Conclusion: This study unveiled the regulatory function and related mechanism of RNase L and implied the promising application of therapeutics targeting RNase L in lung cancer.

Oncogenesis ; 8(10): 59, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597912


Chemoresistance has been the biggest obstacle in ovarian cancer treatment, and STAT3 may play an important role in chemoresistance of multiple cancers, but the underlying mechanism of STAT3 in ovarian cancer chemoresistance has long been truly illusive, particularly in association with p53 and RAS signaling. In this study, by using wild type, constitutive active, and dominant negative STAT3 constructs, wild-type p53, and RAS-mutant V12, we performed a series of in vitro and in vivo experiments by gene overexpression, drug treatment, and animal assays. We found that phosphorylation of STAT3 Y705 but not S727 promoted cancer cell EMT and metastasis through the Slug-mediated regulation of E-cadherin and Vimentin. The phosphorylation of STAT3 at Y705 also activated the MAPK and PI3K/AKT signaling to inhibit the ERS-mediated autophagy through down-regulation of pPERK, pelf2α, ATF6α, and IRE1α, which led to increased cisplatin resistance. Induction of wild type p53 in STAT3-DN-transfected cells further diminished the chemoresistance and tumor growth through the upregulation of the MAPK- and PI3K/AKT-mediated ERS and autophagy. Introduction of STAT3-DN deprived the RASV12-induced ERS, autophagy, oncogenicity, and cisplatin resistance, whereas introduction of p53 in STAT3-DN/RASV12 expressing cells induced additional tumor retardation and cisplatin sensitivity. Thus, our data provide strong evidence that the crosstalk between STAT3 and p53/RAS signaling controls ovarian cancer cell metastasis and cisplatin resistance via the Slug/MAPK/PI3K/AKT-mediated regulation of EMT and autophagy.

Cell Death Dis ; 10(9): 642, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501431


RNase L is an essential component in interferon (IFN)-mediated antiviral signaling that showed antitumor effects in cancer. Cancer immunotherapy based on interferon has achieved encouraging results that indicate an applicable potential for cancer therapy. Here we showed that function of RNase L, though highly upregulated, was functionally impaired both in nuclear and cytoplasm in lung cancer cells. In normal lung epithelial cells, RNase L activation induced by 2-5A promoted nuclear condensation, DNA cleavage, and cell apoptosis, while in lung cancer cells, these processes were inhibited and RNase L-mediated downregulation of fibrillarin, Topo I and hnRNP A1 was also impaired in lung cancer cells. Moreover, the impairment of RNase L in lung cancer cells was due to the elevated expression of RLI. Application of IFN-γ to lung cancer cells led to enhanced expression of RNase L that compensated the RLI inhibition and restored the cytoplasmic and nuclear function of RNase L, leading to apoptosis of lung cancer cells. Thus, the present study discovered the impaired function and mechanism of RNase L in lung cancer cells and proved the efficacy of IFN-γ in restoring RNase L function and inducing apoptosis in the lung cancer cell. These results indicated the RNase L as a therapeutic target in lung cancer cells and immunotherapy of IFN-γ may serve as an adjuvant to enhance the efficacy.

Cancer Med ; 7(11): 5488-5496, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30306725


Postoperative chemotherapy has been widely used in the treatment of early-staged ovarian cancer patients underwent unilateral resection, but the clinical decision mainly depends on the doctor's experience without a well-defined guideline. This study used propensity score matching to analyze the effect of postoperative chemotherapy for early-staged ovarian cancer patients underwent unilateral resection on prognosis. Patients of age 50 or younger than 50 with early-staged ovarian cancer were explored from the Surveillance, Epidemiology, and End Results program database during 2000-2018. Propensity score matching was used to randomize the dataset and reduce the selection biases. Univariate and multivariate cox proportional hazards models were utilized to estimate the necessity of chemotherapy. In univariate analysis of matched population, both the overall survival and cancer-specific survival analysis showed that chemotherapy had no effect on the prognosis of early-staged young ovarian cancer patients (Overall survival, P = 0.477; Cancer-specific survival, P = 0.950). In propensity-adjusted multivariate analysis, chemotherapy still had no effect on both the overall and cancer-specific survival probability after excluding the effect of all the confounding factors (HR = 0.863, CI = 0.587-1.269, P = 0.455; HR = 1.009, CI = 0.633-1.607, P = 0.970). Our study suggested that postoperative chemotherapy is not necessary for early-staged young ovarian cancer patients with unilateral resection, as indicated by both the overall survival and cancer-specific survival.

Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Adulto , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Prognóstico , Programa de SEER , Análise de Sobrevida