STAT3:FOXM1 and MCT1 drive uterine cervix carcinoma fitness to a lactate-rich microenvironment
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Uterine cervix cancer is the second most common malignancy in women worldwide with human papillomavirus (HPV) as the etiologic factor. The two main histological variants, squamous cell carcinomas (SCC) and adenocarcinomas (AC), resemble the cell morphology of exocervix and endocervix, respectively. Cancer metabolism is a cancer hallmark conditioned by the microenvironment. As uterine cervix homeostasis is dependent on lactate, we hypothesized lactate plays a role in uterine cervix cancer progression. Using in vitro (SiHa-SCC and HeLa-AC) and BALB-c/SCID models, we demonstrated that lactate metabolism is linked to histological types, with SCC predominantly consuming and AC producing lactate. MCT1 is a key factor, allowing lactate consumption and being regulated in vitro by lactate through the FOXM1:STAT3 pathway. In vivo models showed that SCC (SiHa) expresses MCT1 and is dependent on lactate to grow, whereas AC (HeLa) expresses MCT1 and MCT4, with higher growth capacities. Immunohistochemical analysis of tissue microarrays (TMA) from human cervical tumors showed that MCT1 expression associates with the SCC type and metastatic behavior of AC, whereas MCT4 expression concomitantly increases from in situ SCC to invasive SCC and is significantly associated with the AC type. Consistently, FOXM1 expression is statistically associated with MCT1 positivity in SCC, whereas the expression of FOXO3a, a FOXM1 functional antagonist, is linked to MCT1 negativity in AC. Our study reinforces the role of the microenvironment in the metabolic adaptation of cancer cells, showing that cells that retain metabolic features of their normal counterparts are positively selected by the organ’s microenvironment and will survive. In particular, MCT1 was shown to be a key element in uterine cervix cancer development; however, further studies are needed to validate MCT1 as a suitable therapeutic target in uterine cervix cancer.
KeywordsUterine cervix cancer MCT1 Metabolic symbiosis STAT3-FOXM1 New therapeutic target
The project was funded by Fundação Luso-Americana para o Desenvolvimento (Project FLAD No. 097/2011; PI Jacinta Serpa) and Fundação para a Ciência e a Tecnologia (PTDC\BIM-ONC\1242\2012). The authors would like to thank the Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE (IPOLFG, EPE), for partially supporting the project. The NMR spectrometers are part of the National NMR Facility supported by Fundação para a Ciência e a Tecnologia (RECI/BBB-BQB/0230/2012). Luis G Goncalves acknowledges the grant from the project RECI/BBB-BQB/0230/2012 of Fundação para a Ciência e a Tecnologia.
Compliance with ethical standards
The animal handling and experimental procedures were performed under the rules of the Federation for Laboratory Animal Science Associations (FELASA), accomplishing the 3Rs through evidence-based guidelines.
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