Shun‐Fa Yang

The association between endometrial cancer and subsequent diabetic retinopathy severity: A retrospective nationwide study

AbstractObjectiveThe endometrial cancer is a disorder with elevated oxidative stress. The high oxidative stress resulting from hyperglycemia can lead to diabetic retinopathy (DR) development which is a complication of type 2 diabetes mellitus. Accordingly, we aim to evaluate the potential relationship between the endometrial cancer and following DR development.MethodsA retrospective cohort study was conducted using the National Health Insurance Research Database (NHIRD) of Taiwan. Individuals diagnosed with endometrial cancer were matched to the non‐endometrial cancer patients in a 1:4 ratio. The major outcomes are the presence of DR, diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) according to diagnostic codes. Cox proportional hazard regression was used to show the adjusted hazard ratio (aHR) with 95% confidence interval (CI) of major outcomes between groups.ResultsThere were 99 (2.3%), 20 (0.5%), and 14 (0.3%) cases with DR, DME and PDR in the endometrial cancer group, respectively. Another 303 (1.8%), 35 (0.2%), and 27 (0.2%) with DR, DME and PDR were observed in the control group, respectively. The endometrial cancer group revealed a significantly higher incidence of DR compared with the control group (aHR 1.51, 95% CI 1.20–1.90, P < 0.001). The cumulative probability of DR was also higher in the endometrial cancer group than in the control group (P < 0.001). The relationship between endometrial cancer and DR was significantly higher in patients aged over 70 years (P = 0.008). In addition, a higher incidence of DR was found during the first 5 years after the endometrial cancer diagnosis (P < 0.001).ConclusionsThe endometrial cancer correlates to a higher incidence of subsequent DR, especially within first 5 years of endometrial cancer diagnosis.

Risk Prediction of Second Primary Endometrial Cancer in Obese Women: A Hospital-Based Cancer Registry Study

Due to the high effectiveness of cancer screening and therapies, the diagnosis of second primary cancers (SPCs) has increased in women with endometrial cancer (EC). However, previous studies providing adequate evidence to support screening for SPCs in endometrial cancer are lacking. This study aimed to develop effective risk prediction models of second primary endometrial cancer (SPEC) in women with obesity (body mass index (BMI) > 25) and included datasets on the incidence of SPEC and the other risks of SPEC in 4480 primary cancer survivors from a hospital-based cancer registry database. We found that obesity plays a key role in SPEC. We used 10 independent variables as predicting variables, which correlated to obesity, and so should be monitored for the early detection of SPEC in endometrial cancer. Our proposed scheme is promising for SPEC prediction and demonstrates the important influence of obesity and clinical data representation in all cases following primary treatments. Our results suggest that obesity is still a crucial risk factor for SPEC in endometrial cancer.

Molecular Mechanisms Underlying the Anticancer Properties of Pitavastatin against Cervical Cancer Cells

Cervical cancer ranks as the fourth most prevalent form of cancer and is a significant contributor to female mortality on a global scale. Pitavastatin is an anti-hyperlipidemic medication and has been demonstrated to exert anticancer and anti-inflammatory effects. Thus, the purpose of this study was to evaluate the anticancer effect of pitavastatin on cervical cancer and the underlying molecular mechanisms involved. The results showed that pitavastatin significantly inhibited cell viability by targeting cell-cycle arrest and apoptosis in Ca Ski, HeLa and C-33 A cells. Pitavastatin caused sub-G1- and G0/G1-phase arrest in Ca Ski and HeLa cells and sub-G1- and G2/M-phase arrest in C-33 A cells. Moreover, pitavastatin induced apoptosis via the activation of poly-ADP-ribose polymerase (PARP), Bax and cleaved caspase 3; inactivated the expression of Bcl-2; and increased mitochondrial membrane depolarization. Furthermore, pitavastatin induced apoptosis and slowed the migration of all three cervical cell lines, mediated by the PI3K/AKT and MAPK (JNK, p38 and ERK1/2) pathways. Pitavastatin markedly inhibited tumor growth in vivo in a cancer cell-originated xenograft mouse model. Overall, our results identified pitavastatin as an anticancer agent for cervical cancer, which might be expanded to clinical use in the future.

Deoxyshikonin triggers apoptosis in cervical cancer cells through p38 MAPK ‐mediated caspase activation

Abstract Deoxyshikonin (DSK) is a biological component derived from Lithospermum erythrorhizon . Although DSK possesses potential anticancer activities, whether DSK exerts anticancer effects on cervical cancer cells is incompletely explored. This study was aimed to investigate the anticancer activity of DSK against cervical cancer cells and its molecular mechanisms. Cell viability was evaluated by MTT assay. Level of phosphorylation and protein was determined using Western blot. Involvement of signaling kinases was assessed by specific inhibitors. Our results revealed that DSK reduced viability of human cervical cell in a dose‐dependent fashion. Meanwhile, DSK significantly elicited apoptosis of HeLa and SiHa cells. Apoptosis microarray was used to elucidate the involved pathways, and the results showed that DSK dose‐dependently diminished cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, and XIAP, and induced cleavage of poly(ADP‐ribose) polymerase (PARP) and caspase‐8/9/3. Furthermore, we observed that DSK significantly triggered activation of ERK, JNK, and p38 MAPK (p38), and only inhibition of p38 diminished the DSK‐mediated pro‐caspases cleavage. Taken together, our results demonstrate that DSK has anti‐cervical cancer effects via the apoptotic cascade elicited by downregulation of IAPs and p38‐mediated caspase activation. This suggests that DSK could act as an adjuvant to facilitate cervical cancer management.

Different Influences of Endometriosis and Pelvic Inflammatory Disease on the Occurrence of Ovarian Cancer

To compare the rate and risk of ovarian cancer in patients with endometriosis or pelvic inflammatory disease (PID). A nationwide population cohort research compared the risk of ovarian cancer in 135,236 age-matched comparison females, 114,726 PID patients, and 20,510 endometriosis patients out of 982,495 females between 1 January 2002 and 31 December 2014 and ended on the date of confirmation of ovarian cancer, death, or 31 December 2014. In order to reduce the unbalanced characteristics, propensity score matching (PSM) was performed for 20,478 females in each subgroup. The incidence rate (per 100,000 person–years) of ovarian cancer was 8.74 (95% CI, 7.16–10.66) in comparison, 9.26 (7.54–11.39) in PID, and 28.73 (21.07–39.16) in endometriosis cohorts. The adjusted hazard ratio (aHR) of ovarian cancer was 1.17 (p = 0.296) in PID and 3.12 (p < 0.001) in endometriosis cohorts, compared with the comparison cohort in full cohort, using the multiple Cox regression model. The aHR of ovarian cancer was 0.83 (p = 0.650) in PID and 3.03 (p = 0.001) in endometriosis cohorts, compared with the comparison cohort after performing PSM. In the full cohort and PSM population, the cumulative incidence rate of ovarian cancer was significantly higher in patients with endometriosis than in those with PID or in the comparison cohort (p < 0.001 and p < 0.001). In conclusion, after considering the differences in the impacts of exposure to endometriosis or PID, patients with endometriosis were more likely to develop ovarian cancer.

Dioscorea nipponicaMakino suppressesTPA‐induced migration and invasion through inhibition of matrix metalloproteinase‐9 in human cervical cancer cells

AbstractDioscorea nipponicaMakino has been used for the treatment of chronic bronchitis, rheumatoid arthritis, cough, and asthma. Several studies have established the antitumor effect ofD. nipponicaMakino extract (DNE). However, no investigations have considered the antimetastatic potential of DNE in cervical cancer cells. The present study examined the effects of DNE on cervical cancer cells treated with 12‐O‐tetradecanoylphorbol‐13‐acetate and characterized the possible molecular mechanisms. MTT assay results indicated that DNE exhibited very low cytotoxicity, and DNE significantly reduced the invasion and migration abilities of cervical cancer cells. Gelatin zymography analysis revealed that DNE significantly inhibited matrix metalloproteinase‐9 (MMP‐9) activity. Reverse transcription‐polymerase chain reaction assay results revealed that DNE treatment inhibited the MMP‐9 mRNA levels of HeLa and SiHa cells. Western blot results revealed that DNE significantly diminished the ERK1/2 phosphorylation. In conclusion, we revealed that the antimetastatic effects of DNE on cervical cancer cells are due to its inhibition of MMP‐9 expression through the ERK1/2 pathway.

MTA2 silencing attenuates the metastatic potential of cervical cancer cells by inhibiting AP1-mediated MMP12 expression via the ASK1/MEK3/p38/YB1 axis

AbstractMetastasis-associated protein 2 (MTA2) is a transcription factor that is highly associated with matrix metalloproteinase 12 (MMP12). Thus, we hypothesized that MTA2 may regulate MMP12 expression and is involved in cervical cancer metastasis. Results showed that MTA2 and MMP12 were highly expressed in cervical cancer cells, and MTA2 knockdown reduced MMP12 expression and inhibited the metastasis of cervical cancer cells in xenograft mice. MMP12 knockdown did not influence the viability of cervical cancer cells but clearly inhibited cell migration and invasion both in vitro and in vivo. MMP12 was highly expressed in cervical tumor tissues and correlated with the poor survival rate of patients with cervical cancer. Further investigations revealed that p38 mitogen-activated protein kinase (p38), mitogen-activated protein kinase kinase 3 (MEK3), and apoptosis signal-regulating kinase 1 (ASK1) were involved in MMP12 downregulation in response to MTA2 knockdown. Results also demonstrated that p38-mediated Y-box binding protein1 (YB1) phosphorylation disrupted the binding of AP1 (c-Fos/c-Jun) to the MMP12 promoter, thereby inhibiting MMP12 expression and the metastatic potential of cervical cancer cells. Collectively, targeting both MTA2 and MMP12 may be a promising strategy for the treatment of cervical cancer.

Dihydromyricetin Inhibited Migration and Invasion by Reducing S100A4 Expression through ERK1/2/β-Catenin Pathway in Human Cervical Cancer Cell Lines

Cervical cancer has a poor prognosis and is the fourth most common cancer among women. Dihydromyricetin (DHM), a flavonoid compound, exhibits several pharmacological activities, including anticancer effects; however, the effects of DHM on cervical cancer have received insufficient research attention. This study examined the antitumor activity and underlying mechanisms of DHM on human cervical cancer. Our results indicated that DHM inhibits migration and invasion in HeLa and SiHa cell lines. Mechanistically, RNA sequencing analysis revealed that DHM suppressed S100A4 mRNA expression in HeLa cells. Moreover, DHM inhibited the protein expressions of β-catenin and GSK3β through the regulated extracellular-signal-regulated kinase (ERK)1/2 signaling pathway. By using the ERK1/2 activator, T-BHQ, reverted β-catenin and S100A4 protein expression and cell migration, which were reduced in response to DHM. In conclusion, our study indicated that DHM inhibited cell migration by reducing the S100A4 expression through the ERK1/2/β-catenin pathway in human cervical cancer cell lines.

EF‐24 inhibits TPA‐induced cellular migration and MMP‐9 expression through the p38 signaling pathway in cervical cancer cells

AbstractDiphenyl difluoroketone (EF‐24), a synthetic curcumin analog, has enhanced bioavailability over curcumin. EF‐24 acts more powerful bioactivity for anti‐inflammatory and anti‐cancer activity. However, the effects and mechanism of EF‐24 on cervical cancer has not been fully investigated. Herein, this study evaluated the effects of EF‐24 on TPA‐induced cellular migration of cervical cancer. The results showed that EF‐24 substantially reduced the cellular migration and cellular invasion of the HeLa and SiHa cells. Moreover, gelatin zymography, western blotting analyses and real‐time PCR revealed that EF‐24 suppressed Matrix metalloproteinase‐9 (MMP‐9) activity, protein expression and mRNA levels. Mechanistically, EF‐24 inhibited the phosphorylation of the p38 signaling pathway. In conclusion, EF‐24 inhibited TPA‐induced cellular migration and cellular invasion of cervical cancer cell lines through modulating MMP‐9 expression via downregulating signaling p38 pathway and EF‐24 may have potential to serve as a chemopreventive agent of cervical cancer.

Magnolin targeting of the JNK/Sp1/MMP15 signaling axis suppresses cervical cancer microenvironment and metastasis via microbiota modulation

Magnolin (MGL), a compound derived from the magnolia plant, has inhibitory effects on tumor cell invasion and growth. His study aims to explore the antitumor effect and underlying molecular mechanism of MGL against human cervical cancer. We found that MGL inhibited the proliferation, migration, and invasiveness of cervical cancer cells in vitro and in vivo. The underlying mechanism was shown to involve MGL-induced inhibition of JNK/Sp1-mediated MMP15 transcription and translation. Overexpression of JNK/Sp1 resulted in significant restoration of MMP15 expression and the migration and invasion capabilities of MGL-treated cervical cancer cells. MGL modulated the cervical cancer microenvironment by inhibiting cell metastasis via targeting IL-10/IL-10 receptor B (IL-10RB) expression, thereby attenuating JNK/Sp1-mediated MMP15 expression. Analysis of the gut microbiota of mice fed MGL revealed a significant augmentation in Lachnospiraceae bacteria, known for their production of sodium butyrate. In vivo experiments also demonstrated synergistic inhibition of cervical cancer cell metastasis by MGL and sodium butyrate co-administration. Our study provides pioneering evidence of a novel mechanism by which MGL inhibits tumor growth and metastasis through the IL-10/IL-10RB targeting of the JNK/Sp1/MMP15 axis in human cervical cancer cells.