Rationale:
Psychological stress has been linked to cancer development and resistance to therapy by many epidemiological and clinical studies. Stress-induced immunosuppressive microenvironment by stress hormones, in particular glucocorticoids, has been extensively studied. However, the impacts of other stress-related neurotransmitters, such as serotonin (5-hydroxytryptamine, 5-HT), on cancer development just start to be revealed. Here, we aimed to identify novel neurotransmitters involved in stress-induced growth and dissemination of ovarian cancer (OC) and reveal the major underlying signaling pathway and the therapeutic significance.
Methods:
Through a genome-wide CRISPR/Cas9 knockout screen in the murine orthotopic model of ovarian carcinoma (OC), we identified candidate genes regulating the peritoneal dissemination of OC. Among them, we picked out HTR1E, one member of 5-HT receptor family specifically expressed in the ovary and endometrium in addition to brain. The correlation of HTR1E expression with OC progression was analyzed in OC patient specimen by quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry (IHC). Gain-of-function and loss-of-function analyses were performed to explore the functions of 5-HT/HTR1E signaling in OC growth and dissemination
in vitro
and
in vivo
. In addition, we investigated the therapeutic values of HTR1E specific agonist and small molecular inhibitors against HTR1E downstream factor SRC in a stressed murine OC xenograft model.
Results:
In OC patients, the HTR1E expression is dramatically decreased in peritoneal disseminated OC cells, which correlates with poor clinical outcome. Silence of HTR1E in OC cells greatly promotes cell proliferation and epithelial mesenchymal transition (EMT) by the activation of SRC-mediated downstream signaling pathways. Furthermore, chronic stress results in significantly decreased serotonin in the ovary and the enhanced OC growth and peritoneal dissemination in mice, which can be strongly inhibited by specific HTR1E agonist or the SRC inhibitor.
Conclusions:
We discovered the essential role of serotonin/HTR1E signaling in preventing the chronic psychological stress-promoted progression of OC, suggesting the potential therapeutic value of the HTR1E specific agonist and the SRC inhibitor for OC patients who are suffering from psychological stress.
Cortactin (CTTN) is overexpressed in various tumors, including head and neck squamous cell carcinoma and colorectal cancer (CRC), and can serve as a biomarker of cancer metastasis. We observed that CTTN promotes cancer cell proliferation in vitro and increases CRC tumor xenograft growth in vivo. CTTN expression increases EGFR protein levels and enhances the activation of the MAPK signaling pathway. CTTN expression also inhibits the ubiquitin-mediated degradation of EGFR by suppressing the coupling of c-Cbl with EGFR. CoIP experiments indicate CTTN can interact with c-Cbl in CRC cells. These results demonstrate that CTTN promotes the proliferation of CRC cells and suppresses the degradation of EGFR.
Acitretin has been a valuable option for the treatment of psoriasis, however, the molecular events of acitretin leading to the normalization of keratinocytes differentiation on psoriasis patients have not been fully explored. To investigate whether there were certain relationship between keratinocytes proliferation and JAK/STAT signaling pathways in psoriasis, and how acitretin modulated the signaling pathways. HaCaT cells, an in vitro immortal human keratinocyte cell line, was chosen as a in vitro model of psoriasis. The small interfering RNA targeting STAT1 (siRNA-STAT1) and STAT3 (siRNA-STAT3) were subsequently transfected into the HaCaT cells which were treated with or without acitretin. We found that HaCaT cells proliferation and the expression of STAT1 or STAT3 were inhibited by acitretin, siRNA-STAT1 and siRNA-STAT3. Our experimental data shows that acitretin might inhibit HaCaT cells proliferation in psoriasis by decreasing the expression of STAT- and STAT3-dependent mechanism.
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