Marcela Angelica De la Fuente-Hernandez1,2, Erika Claudia Alanis-Manriquez2, Eduardo Ferat-Osorio3, Arturo Rodriguez-Gonzalez3, Lourdes Arriaga-Pizano4, Karla Vazquez-Santillan2, Jorge Melendez-Zajgla5, Veronica Fragoso-Ontiveros6, Rosa Maria Alvarez-Gomez6, Vilma Maldonado Lagunas7,8. 1. Facultad de Medicina, Posgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico (UNAM), Av. Ciudad Universitaria 3000, C.P. 04510, Coyoacan, Mexico City, Mexico. 2. Epigenetics Laboratory, Instituto Nacional de Medicina Genomica (INMEGEN), Periferico Sur No. 4809, Col. Arenal Tepepan, Tlalpan, C.P, 14610, Mexico City, Mexico. 3. Gastrosurgery Service, UMAE. Hospital de Especialidades Dr. Bernardo Sepulveda Gutierrez of the Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Av. Cuauhtemoc No 330, Col. Doctores, Cuauhtemoc, C.P., 06720, Mexico City, Mexico. 4. Unidad de Investigacion Medica en Inmunoquimica. Hospital de Especialidades, Dr. Bernardo Sepulveda Gutierrez of the Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Av. Cuauhtemoc No 330, Col. Doctores, Cuauhtemoc, C.P., 06720, Mexico City, Mexico. 5. Functional Cancer Genomics Laboratory, Instituto Nacional de Medicina Genomica (INMEGEN), Periférico Sur No. 4809, Col. Arenal Tepepan, Tlalpan, C.P., 14610, Mexico City, Mexico. 6. National Cancer Institute, San Fernando 22, Seccion XVI, Tlalpan, Mexico City, Mexico. 7. Facultad de Medicina, Posgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico (UNAM), Av. Ciudad Universitaria 3000, C.P. 04510, Coyoacan, Mexico City, Mexico. vmaldonado@inmegen.gob.mx. 8. Epigenetics Laboratory, Instituto Nacional de Medicina Genomica (INMEGEN), Periferico Sur No. 4809, Col. Arenal Tepepan, Tlalpan, C.P, 14610, Mexico City, Mexico. vmaldonado@inmegen.gob.mx.
Abstract
PURPOSE: Obesity is as an important risk factor and has been associated with a worse prognosis in at least 13 distinct tumor types. This is partially due to intercellular communication between tumor cells and adipose tissue-derived stem cells (ADSCs), which are increased in obese individuals. As yet, however, little is known about the molecular changes occurring in ADSCs in these conditions. Cervical cancer has a high incidence and mortality rate in women from developing countries, particularly in those with a high body mass index (BMI). METHODS: We analyzed the expression profile of ADSCs co-cultured with cervical cancer cells through massive RNA sequencing followed by evaluation of various functional alterations resulting from the modified transcriptome. RESULTS: A total of 761 coding and non-coding dysregulated RNAs were identified in ADSCs after co-culture with HeLa cells (validation in CaSki and SiHA cells). Subsequent network analysis showed that these changes were correlated with migration, stemness, DNA repair and cytokine production. Functional experiments revealed a larger ALDHhigh subpopulation and a higher migrative capacity of ADSCs after co-culture with HeLa cells. Interestingly, CXCL3 and its intragenic long-noncoding RNA, lnc-CXCL3, were found to be co-regulated during co-culture. A loss-of-function assay revealed that lnc-CXCL3 acts as a key regulator of CXCL3 expression. CONCLUSIONS: Our results suggest that intercellular communication between ADSCs and cervical cancer cells modifies the RNA expression profile in the former, including that of lncRNAs, which in turn can regulate the expression of diverse chemokines that favor malignancy-associated capacities such as migration.
PURPOSE: Obesity is as an important risk factor and has been associated with a worse prognosis in at least 13 distinct tumor types. This is partially due to intercellular communication between tumor cells and adipose tissue-derived stem cells (ADSCs), which are increased in obese individuals. As yet, however, little is known about the molecular changes occurring in ADSCs in these conditions. Cervical cancer has a high incidence and mortality rate in women from developing countries, particularly in those with a high body mass index (BMI). METHODS: We analyzed the expression profile of ADSCs co-cultured with cervical cancer cells through massive RNA sequencing followed by evaluation of various functional alterations resulting from the modified transcriptome. RESULTS: A total of 761 coding and non-coding dysregulated RNAs were identified in ADSCs after co-culture with HeLa cells (validation in CaSki and SiHA cells). Subsequent network analysis showed that these changes were correlated with migration, stemness, DNA repair and cytokine production. Functional experiments revealed a larger ALDHhigh subpopulation and a higher migrative capacity of ADSCs after co-culture with HeLa cells. Interestingly, CXCL3 and its intragenic long-noncoding RNA, lnc-CXCL3, were found to be co-regulated during co-culture. A loss-of-function assay revealed that lnc-CXCL3 acts as a key regulator of CXCL3 expression. CONCLUSIONS: Our results suggest that intercellular communication between ADSCs and cervical cancer cells modifies the RNA expression profile in the former, including that of lncRNAs, which in turn can regulate the expression of diverse chemokines that favor malignancy-associated capacities such as migration.
Authors: M Dominici; K Le Blanc; I Mueller; I Slaper-Cortenbach; Fc Marini; Ds Krause; Rj Deans; A Keating; Dj Prockop; Em Horwitz Journal: Cytotherapy Date: 2006 Impact factor: 5.414