UCP2 expression may represent a predictive marker of neoadjuvant chemotherapy effectiveness for locally advanced uterine cervical cancer

Imai, Kenji; Fukuda, Takahiro; Wada, Takuya; Kawanishi, Masaru; Tasaka, Reiko; Yasui, Toshihiro; Sumi, Toshiyuki

doi:10.3892/ol.2017.6212

Cited by 18 publications

(11 citation statements)

References 31 publications

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“…Hence, high-risk predictors must be identified to enable stratified management. Filamin A (FLNa) can be used as a predictor of chemotherapy sensitivity and as a biomarker of prognosis ( 11 ), and uncoupling protein 2 (UCP2) can be used as an indicator of chemotherapy sensitivity in patients with advanced CC ( 12 ). The present study focused on FLNa and UCP2 and investigated their expression levels in CC, their roles in the development and progression of CC, and their value for early diagnosis and prognosis prediction of CC.…”

Section: Introductionmentioning

confidence: 99%

Role and mechanism of FLNa and UCP2 in the development of cervical cancer

et al. 2020

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Recent studies have reported that filamin A (FLNa) and uncoupling protein 2 (UCP2) are highly expressed in various types of cancer, but little is currently known about their roles in cervical cancer (CC). In the present study, immunohistochemical staining of paraffin sections of cervical tissues was performed in order to compare the differential expression of FLNa, UCP2, p16 and Ki67 between CC and high-grade intraepithelial neoplasia (HSIL). UCP2 and FLNa were knocked down in CC cell lines to investigate the effects on cell proliferation, cell cycle arrest, apoptosis, migration and invasion. In addition, the present study investigated the expression of cell-associated proteins [extracellular signal-regulated kinase (ERK), phosphorylated (p) ERK, protein kinase B (AKT), p-AKT and B-cell lymphoma-2 (Bcl-2)] and the mRNA levels of cellular proteins such as Ras, matrix metalloproteinase (MMP)-2 and MMP-9. FLNa and UCP2 expression levels were significantly higher in CC tissues than in HSIL tissues, with no significant differential expression of p16 or Ki67. UCP2 expression was significantly different in patients with clinical stage II or higher or lymph node metastasis compared with in other patients with cervical cancer. FLNa or UCP2 knockdown slowed or decreased SiHa and HeLa cell proliferation, migration and invasion, with no significant change in apoptosis, and downregulated the protein levels of p-ERK1/2, and the mRNA levels of Ras, MMP-2 and MMP-9. UCP2 knockdown arrested the cell cycle at the G 2 phase in SiHa and HeLa cells, while FLNa knockdown arrested the cell cycle at the G 2 phase in HeLa cells. The results of the present study revealed that FLNa and UCP2 play roles in the development and progression of CC via the Ras/MAPK/ERK signalling pathway. FLNa and UCP2 are superior to p16 and Ki67 for early prediction of CC, indicating that FLNa and UCP2 may be used for the early diagnosis of CC. UCP2 may be used to predict the prognosis of CC.

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Section: Introductionmentioning

confidence: 99%

Role and mechanism of FLNa and UCP2 in the development of cervical cancer

et al. 2020

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“…For patients that do not respond to NACT, hysterectomy cannot be performed; consequently, the treatment strategy must be changed from surgery to radiation therapy, which results in a long period treatment delay, affecting prognosis (8)(9)(10). Therefore, it is important to identify prognostic factors in patients with LACC that predict whether NACT will be efficient before treatment (11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Expression of HIF‑1α is a predictive marker of the efficacy of neoadjuvant chemotherapy for locally advanced cervical cancer

Yan

Tan

et al. 2020

Oncol Lett

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Platinum-based, arterial infusion chemotherapy as a neoadjuvant chemotherapy (NACT) followed by hysterectomy may be efficient for the treatment of locally advanced cervical cancer and improve prognosis. It is important to predict whether the NACT would be effective before it is launched. Hypoxia inducible factor-1α (HIF-1α) is the master transcriptional regulator of the cellular response to altered oxygen concentration. HIF-1α protein expression is elevated in numerous human malignancies, contributes to poor disease outcome, and has been reported to induce tumorigenesis and chemoresistance. In the present study, patients with International Federation of Gynecology and Obstetrics stage IIB-IIIB cervical cancer (n=59) between 2008 and 2014 were assessed for HIF-1α expression by immunohistochemistry. Tumor samples were obtained by biopsy before any treatment. A double-path chemotherapy regimen, paclitaxel (intravenous) plus cisplatin (intra-arterial injection into the uterine region), was used as NACT. The patients were then separated into two groups according to NACT response: One group comprised patients with NACT, for whom the response to treatment was efficient resulting in complete/partial remission of the tumor (CR + PR group; n=52), the other group contained patients with NACT, for whom the result of the treatment was a stable/progressive disease (SD + PD group; n=7). HIF-1α expression was tested in paraffin-embedded sections using immunohistochemistry. HIF-1α expression was significantly higher in the SD + PD group compared with the CR + PR group (P=0.029). The overall survival time was significantly longer in the CR + PR group compared with the SD + PD group (P<0.001). When the patients were divided into two groups based on HIF-1α expression levels. Low (weighted score ≤4, n=39) and high (weighted score ≥6, n=20) expression level groups; the low HIF-1α expression group was significantly more susceptible to NACT treatment (P=0.025). Cox hazard analysis revealed that a high level of HIF-1α expression and lymph node metastases were significant independent predictors of poor overall survival (P=0.025, HR=6.354; P=0.020, HR=6.909, respectively). These results indicated that the expression of HIF-1α may be able to predict the efficiency of NACT and may be considered an independent prognostic factor for stage IIB-IIIB cervical cancer.

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“…This could be related to the differential effects of genipin at different doses, for example, in inducing or inhibiting the generation of ROS. Despite this discrepancy, genipin is now widely employed as a standard UCP2-inhibiting drug in various experimental models of ROS generation and in mitochondrial activity studies (e.g., [ 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 ] just to mention few). Many other studies on cancer based on UCP2 inhibition and ROS generation by genipin have also been published (e.g., [ 177 , 190 , 191 ]).…”

Section: Lessons On the Mechanisms Of Actionmentioning

confidence: 99%

Plant-Derived Anticancer Agents: Lessons from the Pharmacology of Geniposide and Its Aglycone, Genipin

Habtemariam

Lentini

2018

Biomedicines

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For centuries, plants have been exploited by mankind as sources of numerous cancer chemotherapeutic agents. Good examples of anticancer compounds of clinical significance today include the taxanes (e.g., taxol), vincristine, vinblastine, and the podophyllotoxin analogues that all trace their origin to higher plants. While all these drugs, along with the various other available therapeutic options, brought some relief in cancer management, a real breakthrough or cure has not yet been achieved. This critical review is a reflection on the lessons learnt from decades of research on the iridoid glycoside geniposide and its aglycone, genipin, which are currently used as gold standard reference compounds in cancer studies. Their effects on tumour development (carcinogenesis), cancer cell survival, and death, with particular emphasis on their mechanisms of actions, are discussed. Particular attention is also given to mechanisms related to the dual pro-oxidant and antioxidant effects of these compounds, the mitochondrial mechanism of cancer cell killing through reactive oxygen species (ROS), including that generated through the uncoupling protein-2 (UCP-2), the inflammatory mechanism, and cell cycle regulation. The implications of various studies for the evaluation of glycosidic and aglycone forms of natural products in vitro and in vivo through pharmacokinetic scrutiny are also addressed.

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UCP2 expression may represent a predictive marker of neoadjuvant chemotherapy effectiveness for locally advanced uterine cervical cancer

Cited by 18 publications

References 31 publications

Role and mechanism of FLNa and UCP2 in the development of cervical cancer

Role and mechanism of FLNa and UCP2 in the development of cervical cancer

Expression of HIF‑1α is a predictive marker of the efficacy of neoadjuvant chemotherapy for locally advanced cervical cancer

Plant-Derived Anticancer Agents: Lessons from the Pharmacology of Geniposide and Its Aglycone, Genipin

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