International Journal of Molecular Sciences

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12 pages, 996 KiB

Open AccessArticle

Diagnostic Performance of Immunohistochemistry Compared to Molecular Techniques for Microsatellite Instability and p53 Mutation Detection in Endometrial Cancer

by Sylvie Streel, Alixe Salmon, Adriane Dheur, Vincent Bours, Natacha Leroi, Lionel Habran, Katty Delbecque, Frédéric Goffin, Clémence Pleyers, Athanasios Kakkos, Elodie Gonne, Laurence Seidel, Frédéric Kridelka and Christine Gennigens

Int. J. Mol. Sci. 2023, 24(5), 4866; https://doi.org/10.3390/ijms24054866 - 2 Mar 2023

Cited by 14 | Viewed by 2734

Abstract

Molecular algorithms may estimate the risk of recurrence and death for patients with endometrial cancer (EC) and may impact treatment decisions. To detect microsatellite instabilities (MSI) and p53 mutations, immunohistochemistry (IHC) and molecular techniques are used. To select the most appropriate method, and [...] Read more.

Molecular algorithms may estimate the risk of recurrence and death for patients with endometrial cancer (EC) and may impact treatment decisions. To detect microsatellite instabilities (MSI) and p53 mutations, immunohistochemistry (IHC) and molecular techniques are used. To select the most appropriate method, and to have an accurate interpretation of their results, knowledge of the performance characteristics of these respective methods is essential. The objective of this study was to assess the diagnostic performance of IHC versus molecular techniques (gold standard). One hundred and thirty-two unselected EC patients were enrolled in this study. Agreement between the two diagnostic methods was assessed using Cohen’s kappa coefficient. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the IHC were calculated. For MSI status, the sensitivity, specificity, PPV and NPV were 89.3%, 87.3%, 78.1% and 94.1%, respectively. Cohen’s kappa coefficient was 0.74. For p53 status, the sensitivity, specificity, PPV, and NPV were 92.3%, 77.1%, 60.0% and 96.4%, respectively. Cohen’s kappa coefficient was 0.59. For MSI status, IHC presented a substantial agreement with the polymerase chain reaction (PCR) approach. For the p53 status, the moderate agreement observed between IHC and next generation sequencing (NGS) methods implies that they cannot be used interchangeably. Full article

(This article belongs to the Special Issue Chemotherapeutic Agents in Gynecological Cancers: Drug Design, Development and Therapy)

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15 pages, 2632 KiB

Open AccessArticle

HOXB9 Overexpression Confers Chemoresistance to Ovarian Cancer Cells by Inducing ERCC-1, MRP-2, and XIAP

by Dong Hoon Suh, Wook Ha Park, Miseon Kim, Kidong Kim, Jae Hong No and Yong Beom Kim

Int. J. Mol. Sci. 2023, 24(2), 1249; https://doi.org/10.3390/ijms24021249 - 8 Jan 2023

Cited by 5 | Viewed by 2238

Abstract

The purpose of this study was to identify the role of HOXB9 and associated molecular mechanism in acquiring chemoresistance to ovarian cancer cells. After establishing HOXB9-overexpressing cells (HOXB9-OE/SKOV3), cisplatin resistance-induced cells (Cis-R/SKOV3), and an ovarian cancer xenograft mouse model, the effects of HOXB9 [...] Read more.

The purpose of this study was to identify the role of HOXB9 and associated molecular mechanism in acquiring chemoresistance to ovarian cancer cells. After establishing HOXB9-overexpressing cells (HOXB9-OE/SKOV3), cisplatin resistance-induced cells (Cis-R/SKOV3), and an ovarian cancer xenograft mouse model, the effects of HOXB9 were evaluated in vitro and in vivo. Expression levels of ERCC-1, MRP-2, XIAP, and Bax/Bcl-2 were assessed as putative mechanisms mediating chemoresistance. Cisplatin-induced apoptosis was significantly decreased in HOXB9-OE/SKOV3 compared to SKOV3. Cisplatin treatment of SKOV3 strongly induced ERCC-1, MRP-2, and XIAP, and apoptosis was strongly induced through the inhibition of Bcl-2 and activation of Bax. ERCC-1, MRP-2, XIAP, and Bcl-2 were also strongly induced in HOXB9 OE/SKOV3. In contrast to SKOV3, cisplatin treatment alone of HOXB9 OE/SKOV3 did not affect the expression of Bcl-2 and Bax, and consequently, there was no increase in apoptosis. HOXB9 knockdown suppressed the expression of ERCC-1 and XIAP, but did not affect MRP-2 and Bcl-2/Bax expression in HOXB9 OE/SKOV3 and Cis-R/SKOV3, and caused a small increase in apoptosis. Treatment of SKOV3 with both cisplatin and siRNA_HOXB9 led to complete suppression of ERCC-1, MRP-2, and XIAP, and significantly increased apoptosis through inhibition of Bcl-2 expression and activation of Bax. The results observed in Cis-R/SKOV3 were similar to that in HOXB9 OE/SKOV3. Our data suggest that HOXB9 overexpression may cause chemoresistance in ovarian cancer cells by differential induction of ERCC-1, MRP-2, and XIAP depending on the strength of HOXB9 expression through inhibition of the mitochondrial pathway of apoptosis, including Bax/Bcl-2. Full article

(This article belongs to the Special Issue Chemotherapeutic Agents in Gynecological Cancers: Drug Design, Development and Therapy)

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20 pages, 2555 KiB

Open AccessArticle

Decitabine Treatment Induces a Viral Mimicry Response in Cervical Cancer Cells and Further Sensitizes Cells to Chemotherapy

by Alexia Alexandraki and Katerina Strati

Int. J. Mol. Sci. 2022, 23(22), 14042; https://doi.org/10.3390/ijms232214042 - 14 Nov 2022

Cited by 5 | Viewed by 2360

Abstract

Purpose: To investigate the anti-cancer, chemosensitizing and/or immunomodulating effects of decitabine (DAC) to be used as a potential therapeutic agent for the treatment of cervical cancer (CC). Methods: Cervical cancer cell lines were treated with low doses of DAC treatment used as a [...] Read more.

Purpose: To investigate the anti-cancer, chemosensitizing and/or immunomodulating effects of decitabine (DAC) to be used as a potential therapeutic agent for the treatment of cervical cancer (CC). Methods: Cervical cancer cell lines were treated with low doses of DAC treatment used as a single agent or in combination with chemotherapy. End-point in vitro assays were developed as indicators of the anti-cancer and/or immunomodulating effects of DAC treatment in CC cells. These assays include cell viability, cell cycle analysis, apoptosis, induction of a viral-mimicry response pathway, expression of MHC-class I and PD-L1 and chemosensitivity. Results: High and low doses of DAC treatment induced reduction in cell viability in HeLa (HPV18+), CaSki (HPV16+) and C33A (HPV−) cells. Specifically, a time-dependent reduction in cell viability of HeLa and CaSki cells was observed accompanied by robust cell cycle arrest at G2/M phase and alterations in the cell cycle distribution. Decrease in cell viability was also observed in a non-transformed immortal keratinocyte (HaCat) suggesting a non-cancer specific target effect. DAC treatment also triggered a viral mimicry response through long-term induction of cytoplasmic double-stranded RNA (dsRNA) and activation of downstream IFN-related genes in both HPV+ and HPV− cells. In addition, DAC treatment increased the number of CC cells expressing MHC-class I and PD-L1. Furthermore, DAC significantly increased the proportion of early and late apoptotic CC cells quantified using FACS. Our combination treatments showed that low dose DAC treatment sensitizes cells to chemotherapy. Conclusions: Low doses of DAC treatment promotes robust induction of a viral mimicry response, immunomodulating and chemosensitizing effects in CC, indicating its promising therapeutic role in CC in vitro. Full article

(This article belongs to the Special Issue Chemotherapeutic Agents in Gynecological Cancers: Drug Design, Development and Therapy)

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20 pages, 4383 KiB

Open AccessArticle

Inhibitory Effect of Etravirine, a Non-Nucleoside Reverse Transcriptase Inhibitor, via Anterior Gradient Protein 2 Homolog Degradation against Ovarian Cancer Metastasis

by Thanh Truong Giang Ly, Jisoo Yun, Jong-Seong Ha, Yeon-Ju Kim, Woong-Bi Jang, Thi Hong Van Le, Vinoth Kumar Rethineswaran, Jaewoo Choi, Jae-Ho Kim, Sang-Hyun Min, Dong-Hyung Lee, Ju-Seok Yang, Joo-Seop Chung and Sang-Mo Kwon

Int. J. Mol. Sci. 2022, 23(2), 944; https://doi.org/10.3390/ijms23020944 - 15 Jan 2022

Cited by 9 | Viewed by 2916

Abstract

Anterior gradient protein 2 homolog (AGR2), an endoplasmic reticulum protein, is secreted in the tumor microenvironment. AGR2 is a member of the disulfide isomerase family, is highly expressed in multiple cancers, and promotes cancer metastasis. In this study, we found that etravirine, which [...] Read more.

Anterior gradient protein 2 homolog (AGR2), an endoplasmic reticulum protein, is secreted in the tumor microenvironment. AGR2 is a member of the disulfide isomerase family, is highly expressed in multiple cancers, and promotes cancer metastasis. In this study, we found that etravirine, which is a non-nucleoside reverse transcriptase inhibitor, could induce AGR2 degradation via autophagy. Moreover, etravirine diminished proliferation, migration, and invasion in vitro. Moreover, in an orthotopic xenograft mouse model, the combination of etravirine and paclitaxel significantly suppressed cancer progression and metastasis. This drug may be a promising therapeutic agent for the treatment of ovarian cancer. Full article

(This article belongs to the Special Issue Chemotherapeutic Agents in Gynecological Cancers: Drug Design, Development and Therapy)

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18 pages, 4437 KiB

Open AccessArticle

Inhibition of BIRC2 Sensitizes α7-HPV-Related Cervical Squamous Cell Carcinoma to Chemotherapy

by Chiao-Yun Lin, Chun-Chieh Wang, Ren-Chin Wu, Lan-Yan Yang, Chen-Bin Chang, Yu-Bin Pan, Angel Chao and Chyong-Huey Lai

Int. J. Mol. Sci. 2021, 22(20), 11020; https://doi.org/10.3390/ijms222011020 - 13 Oct 2021

Cited by 4 | Viewed by 2386

Abstract

The α7-human papillomavirus (HPV)-related cervical squamous cell carcinoma (SCC) is associated with poor prognosis. We compared the genomic profiles of this disease in a cohort corresponding to the 2001–2014 period with various responses to radiotherapy or concurrent chemoradiation through microRNA (miR) profiling involving [...] Read more.

The α7-human papillomavirus (HPV)-related cervical squamous cell carcinoma (SCC) is associated with poor prognosis. We compared the genomic profiles of this disease in a cohort corresponding to the 2001–2014 period with various responses to radiotherapy or concurrent chemoradiation through microRNA (miR) profiling involving miR 4.0 array and human transcriptome array 2.0 analyses. A real-time quantitative polymerase chain reaction was then conducted to identify the predictive biomarkers. A significantly lower expression of miR143-3p in recurrent tumors (p = 0.0309) relative to that in nonrecurrent tumors was observed. The miR143-3p targeted the mRNA expression of the baculoviral inhibitor of the apoptosis protein (IAP) repeat-containing 2 (BIRC2; p = 0.0261). The BIRC2 protein levels (p = 0.0023) were significantly higher in recurrent tumors than in nonrecurrent tumors. Moreover, the miR-143-3p sensitized the response of α7-HPV-related cervical SCC to chemotherapy by targeting BIRC2. A combination of BIRC2-inhibitor LCL161 and topotecan exerted synergistic effects on cancer cells and animal tumor models. In a pooled cohort of α7-HPV-related cervical SCC (including mixed infections with non-α7-HPV) treated between 1993 and 2014, high BIRC2 expression was associated with significantly worse outcomes (cancer-specific survival, hazard ratio (HR) = 1.42, p = 0.008; progression-free survival, HR = 1.64; p = 0.005). Summarily, BIRC2 constitutes a novel prognostic factor and therapeutic target for α7-HPV-related cervical SCC. Full article

(This article belongs to the Special Issue Chemotherapeutic Agents in Gynecological Cancers: Drug Design, Development and Therapy)

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15 pages, 34658 KiB

Open AccessArticle

The FGFR Family Inhibitor AZD4547 Exerts an Antitumor Effect in Ovarian Cancer Cells

by Yu Ran Na, Jin Young Kim, Chang Ho Song, Mikyung Kim, Yen Thi Do, Tam Thuy Lu Vo, Eunsom Choi, Eunyoung Ha, Ji Hae Seo and So-Jin Shin

Int. J. Mol. Sci. 2021, 22(19), 10817; https://doi.org/10.3390/ijms221910817 - 6 Oct 2021

Cited by 7 | Viewed by 3069

Abstract

The dysregulation of fibroblast growth factor (FGF) signaling has been implicated in tumorigenesis, tumor progression, angiogenesis, and chemoresistance. The small-molecule AZD4547 is a potent inhibitor of FGF receptors. This study was performed to investigate the antitumor effects and determine the mechanistic details of [...] Read more.

The dysregulation of fibroblast growth factor (FGF) signaling has been implicated in tumorigenesis, tumor progression, angiogenesis, and chemoresistance. The small-molecule AZD4547 is a potent inhibitor of FGF receptors. This study was performed to investigate the antitumor effects and determine the mechanistic details of AZD4547 in ovarian cancer cells. AZD4547 markedly inhibited the proliferation and increased the apoptosis of ovarian cancer cells. AZD4547 also suppressed the migration and invasion of ovarian cancer cells under nontoxic conditions. Furthermore, it attenuated the formation of spheroids and the self-renewal capacities of ovarian cancer stem cells and exerted an antiangiogenic effect. It also suppressed in vivo tumor growth in mice. Collectively, this study demonstrated the antitumor effect of AZD4547 in ovarian cancer cells and suggests that it is a promising agent for ovarian cancer therapy. Full article

(This article belongs to the Special Issue Chemotherapeutic Agents in Gynecological Cancers: Drug Design, Development and Therapy)

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23 pages, 17181 KiB

Open AccessArticle

Promising Anticancer Activity of [Bis(1,8-quinolato)palladium (II)] Alone and in Combination

by Md Nur Alam, Mohammad Ali Moni, Jun Q. Yu, Philip Beale, Peter Turner, Nick Proschogo, Mohammad Azizur Rahman, M. Pear Hossain and Fazlul Huq

Int. J. Mol. Sci. 2021, 22(16), 8471; https://doi.org/10.3390/ijms22168471 - 6 Aug 2021

Cited by 2 | Viewed by 2445

Abstract

Due to similar coordination chemistry of palladium and platinum, a large number of palladium compounds as well have been investigated for their anticancer activity. In the present study, we describe synthesis, characterization, and anticancer activity of palladium complex [Bis(1,8-quinolato)palladium (II)], coded as NH3 [...] Read more.

Due to similar coordination chemistry of palladium and platinum, a large number of palladium compounds as well have been investigated for their anticancer activity. In the present study, we describe synthesis, characterization, and anticancer activity of palladium complex [Bis(1,8-quinolato)palladium (II)], coded as NH3 against seven different cancer cell lines. NH3 is found to have higher antitumor activity than cisplatin against both parent ovarian A2780 cell line and cisplatin-resistant cell lines. Also, NH3 has the lower IC₅₀ value in HT-29 colorectal cancer cell line. The higher antitumor activity of NH3 is due to the presence of bulky 8-Hydroxyquinoline ligand, thus reducing its reactivity. Proteomic study has identified significantly expressed proteins which have been validated through bioinformatics. NH3 has been found to be less toxic than cisplatin at 2.5 mg/kg and 5 mg/kg dosages on mice models. Binary combinations of NH3 with curcumin and epigallocatechin gallate (EGCG) have demonstrated dose and sequence-dependent synergism in ovarian and colorectal cancer models. All of the preclinical studies indicate promising therapeutic potential of NH3 [Bis(1,8-quinolato)palladium (II)] as an anticancer drug. Full article

(This article belongs to the Special Issue Chemotherapeutic Agents in Gynecological Cancers: Drug Design, Development and Therapy)

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Review

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28 pages, 1832 KiB

Open AccessReview

Role of Circulating Biomarkers in Platinum-Resistant Ovarian Cancer

by Carolina Maria Sassu, Innocenza Palaia, Serena Maria Boccia, Giuseppe Caruso, Giorgia Perniola, Federica Tomao, Violante Di Donato, Angela Musella and Ludovico Muzii

Int. J. Mol. Sci. 2021, 22(24), 13650; https://doi.org/10.3390/ijms222413650 - 20 Dec 2021

Cited by 10 | Viewed by 3511

Abstract

Ovarian cancer (OC) is the second most common cause of death in women with gynecological cancer. Considering the poor prognosis, particularly in the case of platinum-resistant (PtR) disease, a huge effort was made to define new biomarkers able to help physicians in approaching [...] Read more.

Ovarian cancer (OC) is the second most common cause of death in women with gynecological cancer. Considering the poor prognosis, particularly in the case of platinum-resistant (PtR) disease, a huge effort was made to define new biomarkers able to help physicians in approaching and treating these challenging patients. Currently, most data can be obtained from tumor biopsy samples, but this is not always available and implies a surgical procedure. On the other hand, circulating biomarkers are detected with non-invasive methods, although this might require expensive techniques. Given the fervent hope in their value, here we focused on the most studied circulating biomarkers that could play a role in PtR OC. Full article

(This article belongs to the Special Issue Chemotherapeutic Agents in Gynecological Cancers: Drug Design, Development and Therapy)

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