RESUMO
The glycoprotein CD44 is a key regulator of malignant behaviors in breast cancer cells. To date, hyaluronic acid (HA)-CD44 signaling pathway has been widely documented in the context of metastatic bone diseases. Core 1 ß1,3-galactosyltransferase (C1GALT1) is a critical enzyme responsible for the elongation of O-glycosylation. Aberrant O-glycans is recognized as a hallmark in cancers. However, the effects of C1GALT1 on CD44 signaling and bone metastasis remain unclear. In this study, IHC analysis indicated that C1GALT1 expression positively correlates with CD44 in breast cancer. Silencing C1GALT1 accumulates the Tn antigen on CD44, which decreases CD44 levels and osteoclastogenic signaling. Mutations in the O-glycosites on the stem region of CD44 impair its surface localization as well as suppress cell-HA adhesion and osteoclastogenic effects of breast cancer cells. Furthermore, in vivo experiments demonstrated the inhibitory effect of silencing C1GALT1 on breast cancer bone metastasis and bone loss. In conclusion, our study highlights the importance of O-glycans in promoting CD44-mediated tumorigenic signals and indicates a novel function of C1GALT1 in driving breast cancer bone metastasis. IMPLICATIONS: Truncation of GalNAc-type O-glycans by silencing C1GALT1 suppresses CD44-mediated osteoclastogenesis and bone metastasis in breast cancer. Targeting the O-glycans on CD44 may serve as a potential therapeutic target for blocking cancer bone metastasis.
Assuntos
Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/genética , Glicosilação , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Osteogênese , Polissacarídeos/metabolismo , Transdução de SinaisRESUMO
Obesity is a risk factor in various types of cancer, including breast cancer. The disturbance of adipose tissue in obesity highly correlates with cancer progression and resistance to standard treatments such as chemo- and radio-therapies. In this study, in a syngeneic mouse model of triple-negative breast cancer (TNBC), diet-induced obesity (DIO) not only promoted tumor growth, but also reduced tumor response to radiotherapy. Serpine1 (Pai-1) was elevated in the circulation of obese mice and was enriched within tumor microenvironment. In vitro co-culture of human white adipocytes-conditioned medium (hAd-CM) with TNBC cells potentiated the aggressive phenotypes and radioresistance of TNBC cells. Moreover, inhibition of both cancer cell autonomous and non-autonomous SERPINE1 by either genetic or pharmacological strategy markedly dampened the aggressive phenotypes and radioresistance of TNBC cells. Mechanistically, we uncovered a previously unrecognized role of SERPINE1 in DNA damage response. Ionizing radiation-induced DNA double-strand breaks (DSBs) increased the expression of SERPINE1 in cancer cells in an ATM/ATR-dependent manner, and promoted nuclear localization of SERPINE1 to facilitate DSB repair. By analyzing public clinical datasets, higher SERPINE1 expression in TNBC correlated with patients' BMI as well as poor outcomes. Elevated SERPINE1 expression and nuclear localization were also observed in radioresistant breast cancer cells. Collectively, we reveal a link between obesity and radioresistance in TNBC and identify SERPINE1 to be a crucial factor mediating obesity-associated tumor radioresistance.
Assuntos
Neoplasias de Mama Triplo Negativas , Animais , Camundongos , Humanos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Linhagem Celular Tumoral , Reparo do DNA , Obesidade/genética , Obesidade/complicações , Quebras de DNA de Cadeia Dupla , Microambiente Tumoral , Inibidor 1 de Ativador de Plasminogênio/genéticaRESUMO
Cellular stress response is an important adaptive mechanism for regulating cell fate decision when cells confront with stress. During tumorigenesis, tumor progression and the course of treatment, cellular stress signaling can activate subsequent response to deal with stress. Therefore, cellular stress response has impacts on the fate of tumor cells and tumor responsiveness relative to therapeutic agents. In recent years, attention has been drawn to long non-coding RNAs (lncRNAs), a novel class of RNA molecules with more than 200 nucleotides in length, which has little protein-coding potential and possesses various functions in multiple biological processes. Accumulating evidence has shown that lncRNAs are also engaged in the regulation of cellular stress response, particularly in cancers. Here, we summarize lncRNAs that have been reported in the adaptive response to major types of cellular stress including genotoxic, hypoxic, oxidative, metabolic and endoplasmic reticulum stress, all of which are often encountered by cancer cells. Specifically, the molecular mechanisms of how lncRNAs regulate cellular stress response during tumor progression or the development of therapy resistance are emphasized. The potential clinical applications of stress-responsive lncRNAs as biomarkers will also be discussed.
