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Spontaneous metastasis xenograft model of human melanoma. (A) Kaplan-Meier overall-survival analysis (OS) for scid mice with subcutaneously injected MeWo cells revealed significantly prolonged OS in mice inoculated with MeWo CEACAM1 kd 1 against MeWo Luc inoculated animals (p < 0.001). (B) Tumor weight at the time of death was not significantly different between the two groups (p = 0.164; n = 11 Luc group and n = 12 CEACAM kd group). (C) Immunohistochemical staining of paraffin embedded tumor tissue (xenograft MeWo tumors in scid mice) for CEACAM1 demonstrated the stability of the CEACAM1 knockdown in the subcutaneous tumors: High CEACAM1 was detected in the MeWo Luc tumors (left panel) whereas little to no CEACAM1 (in red) could be shown in the MeWo CEACAM1 kd tumors (right panel). scale bar: 100 ?m. (D) Knockdown of CEACAM1 significantly decreases metastasis (adj. for survival time and tumor weight; p = 0.016; n = 11 Luc group and n = 10 CEACAM kd group). (E) CEACAM1 knockdown does not significantly alter the number of circulating tumor cells in the blood of scid mice (p = 0.756, n = 10 each group). Quantification of circulating (human) tumor cells in the blood of scid mice inoculated with MeWo CEACAM1 kd (orange) compared with controls (MeWo Luc, teal) by quantitative real-time PCR.
Source publication
We investigated the functional role of CEACAM1 in a spontaneous metastasis xenograft model of human melanoma in scid mice using BRAF wildtype MeWo cells with and without RNAi mediated knockdown of CEACAM1. Tumors from the xenograft model were subjected to whole genome expression analysis and metastasis was quantified histologically. Results and ide...
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... regulation of IGFBP7 and LXN upon CEACAM1 kd could also be demonstrated in cultured MeWo cells by flow cytometry (intracellular staining): The fluorescence signal for LXN was only 31% in the CEACAM1 kd cells (signal above isotype background MeWo CEACAM1 kd: 2.2; MeWo Luc: 7.02) whereas the signal for IGFBP7 was 296% in the CEACAM1 kd cells (signal above isotype background MeWo CEACAM1 kd: 5.48; MeWo Luc: 1.85; Fig. 3C). IGFBP7 and LXN were also up-and downregulated, respectively, in the corresponding lung metastases of the xenograft model ( Supplementary Fig. ...
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... knockdown (CEACAM1 kd) and MeWo Luc cells with unaltered CEACAM1 expression were injected subcutaneously into scid mice (n = 12 each group). One mouse from the Luc group died two days after injection and was therefore excluded from further analyses. All remaining animals developed subcutaneous tum- ors at the injection site and were euthanized when the tumor ulcerated. The tumors in the CEACAM1 kd group ulcerated later than the corresponding Luc tumors: Overall survival (OS; time from inoculation to euthaniza- tion) was significantly longer (+31. Immunohistochemical staining of paraffin embedded tumor tissue demonstrated the stability of the CEACAM1 knockdown in the subcutaneous tumors: Little to no CEACAM1 protein could be shown in the MeWo CEACAM1 kd tumors whereas high CEACAM1 was detected in the MeWo Luc tumors (Fig. ...
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... load (adjusted for survival time and tumor weight) in the Luc control group was 14.7 times higher (95%-CI [2.4;91.3]; p = 0.006) in comparison with the CEACAM1 kd group (Fig. ...
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... was no statistically significant difference in the number of circulating tumor cells between the CEACAM1 kd group and the Luc control group (p = 0.756; Fig. ...
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... expression could be investigated by immunohistochemistry in melanoma from 106 patients. Of these samples, 28 displayed no or low FOSL1 expression (score of 0 or 1; group FOSL1 low) and 78 displayed medium or high FOSL expression (score 2 or 3; group FOSL1 high). High FOSL expression in the melanoma was corre- lated with shortened patient survival (age-adjusted HR 3.2, 95%-CI [1.1;9.1]; p = 0.029) with a 5-year survival of 68.0% (95%-CI [56.4;77.1]) in comparison to 85.7% (95%-CI [66.3;94.4]) for the FOSL1 low patients (Fig. 6D). High expression of CEACAM1 in the melanoma samples correlated with high FOSL1 (? = 0.36, p < 0.001) and also CEACAM1 staining in a certain area of an individual melanoma often correlated with FOSL1 staining inten- sity in the same area (serial sections, e.g. Supplementary Fig. 8). For an isotype control for FOSL1 staining please see Supplementary Fig. 4. FOSL1 expression was also low in the CEACAM1 knockdown lung metastases of the xenograft model (Supplementary Fig. ...
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... of TWIST in the melanoma samples. In the patients' melanoma specimens, single cells in the stratum basale of the epidermis of the normal skin within the samples showed nuclear staining for TWIST (presumably epidermal stem cells). Notably, the staining intensity of these normal epidermal stem cells mark- edly differed between patients. The melanoma cells in the samples also showed nuclear TWIST with staining intensities that could be lower, as high as or even higher (the latter being seldom, 9 cases) than the staining intensities of the epidermal stem cells of the normal skin tissue of the same sample. Nuclear TWIST staining was classified accordingly as 1 (lower than the stem cells), 2 (as high as the stem cells) or 3 (higher than the stem cells). Additionally, the melanoma cells always showed low to very high cytoplasmic staining for TWIST. Accordingly, cytoplasmic TWIST in the melanoma cells was classified as 1 (low), 2 (medium), 3 (high) and 4 (very high). Nuclear and cytoplasmic TWIST staining could be obtained from the melanoma samples of 106 patients. Regarding the samples' melanoma cells, a high quotient of cytoplasmic/nuclear Twist (groups were: low [cytoplasmic-to-nuclear Twist ratio ? 2] and high [cytoplasmic-to-nuclear Twist ratio > 2]) was associated with a higher risk for death in comparison with low proportion of cytoplasmic Twist (age-adjusted HR 2.3, 95%-CI [1. 2;4.3]; p = 0.013). Better prognosis for TWIST cytoplasmic/nuclear low patients comes with a 5-year survival of 80.4% (95%-CI [67.3;88.6]) compared with 56.0% (95%-CI [41.2;68.4]) 5-year survival for the TWIST cyto- plasmic/nuclear high patients (Fig. 6A). High expression of CEACAM1 in the melanoma samples correlated with high cytoplasmic/nuclear Twist (? = 0.20, p = 0.049) and also CEACAM1 staining in a certain area of an individual melanoma often correlated with cytoplasmic/nuclear TWIST staining intensity in the same area (serial sections, e.g. Supplementary Fig. 7). For an isotype control for TWIST staining please see Supplementary Fig. 4. Additionally, cytoplasmic/nuclear Twist was low in the CEACAM1 kd lung metastases of the xenograft model ( Supplementary Fig. ...
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... regulation of IGFBP7 and LXN upon CEACAM1 kd could also be demonstrated in cultured MeWo cells by flow cytometry (intracellular staining): The fluorescence signal for LXN was only 31% in the CEACAM1 kd cells (signal above isotype background MeWo CEACAM1 kd: 2.2; MeWo Luc: 7.02) whereas the signal for IGFBP7 was 296% in the CEACAM1 kd cells (signal above isotype background MeWo CEACAM1 kd: 5.48; MeWo Luc: 1.85; Fig. 3C). IGFBP7 and LXN were also up-and downregulated, respectively, in the corresponding lung metastases of the xenograft model ( Supplementary Fig. ...
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... knockdown (CEACAM1 kd) and MeWo Luc cells with unaltered CEACAM1 expression were injected subcutaneously into scid mice (n = 12 each group). One mouse from the Luc group died two days after injection and was therefore excluded from further analyses. All remaining animals developed subcutaneous tum- ors at the injection site and were euthanized when the tumor ulcerated. The tumors in the CEACAM1 kd group ulcerated later than the corresponding Luc tumors: Overall survival (OS; time from inoculation to euthaniza- tion) was significantly longer (+31. Immunohistochemical staining of paraffin embedded tumor tissue demonstrated the stability of the CEACAM1 knockdown in the subcutaneous tumors: Little to no CEACAM1 protein could be shown in the MeWo CEACAM1 kd tumors whereas high CEACAM1 was detected in the MeWo Luc tumors (Fig. ...
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... load (adjusted for survival time and tumor weight) in the Luc control group was 14.7 times higher (95%-CI [2.4;91.3]; p = 0.006) in comparison with the CEACAM1 kd group (Fig. ...
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... was no statistically significant difference in the number of circulating tumor cells between the CEACAM1 kd group and the Luc control group (p = 0.756; Fig. ...
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... expression could be investigated by immunohistochemistry in melanoma from 106 patients. Of these samples, 28 displayed no or low FOSL1 expression (score of 0 or 1; group FOSL1 low) and 78 displayed medium or high FOSL expression (score 2 or 3; group FOSL1 high). High FOSL expression in the melanoma was corre- lated with shortened patient survival (age-adjusted HR 3.2, 95%-CI [1.1;9.1]; p = 0.029) with a 5-year survival of 68.0% (95%-CI [56.4;77.1]) in comparison to 85.7% (95%-CI [66.3;94.4]) for the FOSL1 low patients (Fig. 6D). High expression of CEACAM1 in the melanoma samples correlated with high FOSL1 (? = 0.36, p < 0.001) and also CEACAM1 staining in a certain area of an individual melanoma often correlated with FOSL1 staining inten- sity in the same area (serial sections, e.g. Supplementary Fig. 8). For an isotype control for FOSL1 staining please see Supplementary Fig. 4. FOSL1 expression was also low in the CEACAM1 knockdown lung metastases of the xenograft model (Supplementary Fig. ...
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... of TWIST in the melanoma samples. In the patients' melanoma specimens, single cells in the stratum basale of the epidermis of the normal skin within the samples showed nuclear staining for TWIST (presumably epidermal stem cells). Notably, the staining intensity of these normal epidermal stem cells mark- edly differed between patients. The melanoma cells in the samples also showed nuclear TWIST with staining intensities that could be lower, as high as or even higher (the latter being seldom, 9 cases) than the staining intensities of the epidermal stem cells of the normal skin tissue of the same sample. Nuclear TWIST staining was classified accordingly as 1 (lower than the stem cells), 2 (as high as the stem cells) or 3 (higher than the stem cells). Additionally, the melanoma cells always showed low to very high cytoplasmic staining for TWIST. Accordingly, cytoplasmic TWIST in the melanoma cells was classified as 1 (low), 2 (medium), 3 (high) and 4 (very high). Nuclear and cytoplasmic TWIST staining could be obtained from the melanoma samples of 106 patients. Regarding the samples' melanoma cells, a high quotient of cytoplasmic/nuclear Twist (groups were: low [cytoplasmic-to-nuclear Twist ratio ? 2] and high [cytoplasmic-to-nuclear Twist ratio > 2]) was associated with a higher risk for death in comparison with low proportion of cytoplasmic Twist (age-adjusted HR 2.3, 95%-CI [1. 2;4.3]; p = 0.013). Better prognosis for TWIST cytoplasmic/nuclear low patients comes with a 5-year survival of 80.4% (95%-CI [67.3;88.6]) compared with 56.0% (95%-CI [41.2;68.4]) 5-year survival for the TWIST cyto- plasmic/nuclear high patients (Fig. 6A). High expression of CEACAM1 in the melanoma samples correlated with high cytoplasmic/nuclear Twist (? = 0.20, p = 0.049) and also CEACAM1 staining in a certain area of an individual melanoma often correlated with cytoplasmic/nuclear TWIST staining intensity in the same area (serial sections, e.g. Supplementary Fig. 7). For an isotype control for TWIST staining please see Supplementary Fig. 4. Additionally, cytoplasmic/nuclear Twist was low in the CEACAM1 kd lung metastases of the xenograft model ( Supplementary Fig. ...
Citations
... These genes are considered as potential metastasis-promoting genes and included Ceacam1, which promotes melanoma metastasis (Table 1). 19 Among these genes, we selected Cntn1, Hfe, Igsf3, Igsf11, and Unc5c due to their unknown functions in metastasis. Each gene was knocked down in B16F10 cells using two independent shRNAs ( Figure 2A). ...
The immunoglobulin superfamily (IgSF) is one of the largest families of cell‐surface molecules involved in various cell–cell interactions, including cancer–stromal interactions. In this study, we undertook a comprehensive RT‐PCR‐based screening for IgSF molecules that promote experimental lung metastasis in mice. By comparing the expression of 325 genes encoding cell‐surface IgSF molecules between mouse melanoma B16 cells and its highly metastatic subline, B16F10 cells, we found that expression of the immunoglobulin superfamily member 3 gene (Igsf3) was significantly enhanced in B16F10 cells than in B16 cells. Knockdown of Igsf3 in B16F10 cells significantly reduced lung metastasis following intravenous injection into C57BL/6 mice. IGSF3 promoted adhesion of B16F10 cells to vascular endothelial cells and functioned as a homophilic cell adhesion molecule between B16F10 cells and vascular endothelial cells. Notably, the knockdown of IGSF3 in either B16F10 cells or vascular endothelial cells suppressed the transendothelial migration of B16F10 cells. Moreover, IGSF3 knockdown suppressed the extravasation of B16F10 cells into the lungs after intravenous injection. These results suggest that IGSF3 promotes the metastatic potential of B16F10 cells in the lungs by facilitating their adhesion to vascular endothelial cells.
... Co-expression of SOX10-CEACAM1 markedly decreases the cancer stem cell pool and CD8 + T-cell infiltration in melanoma CEACAM1 has been shown to play contradictory roles within different cancer types. [47][48][49] To gain insight into the SOX10-CEACAM1-driven phenotypes in melanoma, we sorted our YUMM1.7 pBABE-Sox10 cells into their CEACAM1and CEACAM1 + populations ( Figure 6A). These populations remained stable using flow cytometry for up to 17 days post sorting ( Figure S5A). ...
SOX10 is a key regulator of melanoma progression and promotes a melanocytic/differentiated state. Here we identified melanoma cell lines lacking SOX10 expression which retain their in vivo growth capabilities. More importantly, we find that SOX10 can regulate T-cell infiltration in melanoma while also decreasing common cancer stem cell (CSC) properties. We show that SOX10 regulates CEACAM1, a surface protein with immunomodulatory properties. SOX10 directly binds to a distal CEACAM1 promoter region approximately 3-4kbps from the CEACAM1 transcriptional start site. Furthermore, we show that a SOX10-CEACAM1 axis can suppress CD8+ T-cell infiltration as well as reduce CSC pool within tumors, leading to reduced tumor growth. Overall, these results identify SOX10 as a direct regulator of CEACAM1, and uncover both a pro- and anti-tumorigenic roles for SOX10 in melanoma.
... Response to infection (phagocytosis, oxidative burst, neutrophil extracellular trap [66] Altering composition of immune cells in tumor microenvironment [66] Activation of vascular endothelial cells → cells angiogenesis → ↑ proliferation, migration [67] Activation of vascular endothelial cells → cancer cells angiogenesis → cancer migration [68] Infiltration of immune cells → tumor-reactive cytotoxic mechanism [69] Infiltration of neutrophils and MDSC → immunosuppression [66,70] ↑ growth factor secretion by tumor associated macrophages [68] Lower survival rate in tumor patients [70] EMT induction [66] IGFBP7 ↑CDK inhibitors → cell cycle arrest → tumor suppression [71][72][73] Infiltration of immune cells in gastric cancer [74] ↑ E-cadherin, ↓ N-cadherin, ↓ Vimentin → EMT inhibition [75][76][77] Lower survival rate in gastric cancer patients [74] Higher survival rate in melanoma patients [78] Chemoresistance [79] 3. ...
Cellular senescence process results in stable cell cycle arrest, which prevents cell proliferation. It can be induced by a variety of stimuli including metabolic stress, DNA damage, telomeres shortening, and oncogenes activation. Senescence is generally considered as a process of tumor suppression, both by preventing cancer cells proliferation and inhibiting cancer progression. It can also be a key effector mechanism for many types of anticancer therapies such as chemotherapy and radiotherapy, both directly and through bioactive molecules released by senescent cells that can stimulate an immune response. Senescence is characterized by a senescence-associated secretory phenotype (SASP) that can have both beneficial and detrimental impact on cancer progression. Despite the negatives, attempts are still being made to use senescence to fight cancer, especially when it comes to senolytics. There is a possibility that a combination of prosenescence therapy—which targets tumor cells and causes their senescence—with senotherapy—which targets senescent cells, can be promising in cancer treatment. This review provides information on cellular senescence, its connection with carcinogenesis and therapeutic possibilities linked to this process.
... Globally, disease accounts for approximately 0.03% of all newly diagnosed cancers (5). Previous studies have shown that the high mortality rate is due to the aggressive metastatic potential of melanoma cells (6). Previous estimates have shown that approximately 132,000 and 48,000 new malignant melanoma cases and deaths, respectively, occur each year (7). ...
Melanoma, also known as malignant melanoma, is a type of malignant tumour that originates from melanocytes in the basal layer of the epidermis. Primary malignant melanomas of the female genital tract are rare. Similarly, primary malignant melanoma of cervix, which originates from cervical melanocytes, is an extremely rare disease and the second most common type of female melanoma in women aged between 15 to 44 years worldwide. To date, primary malignant melanoma of the cervix is characterized by poor patient prognosis and little consensus exists regarding the best treatment therapy. The situation is worsened by lack of clinical studies with large samples. Notably, surgery remains the preferred treatment option for patients with primary malignant melanomas of the cervix. Current treatments are based on Federation International of Gynecology and Obstetrics(2018) staging with reference to National Comprehensive Cancer Network guidelines. This study is in order to find a more suitable treatment modality for primary malignant melanoma of cervix. Therefore, we first conducted an integrated analysis of case reports and series to assess the impact of various factors on the prognosis of such patients. In summary, this is the first pooled analysis including 149 cases of primary cervical melanoma. We found that patients who underwent radical hysterectomy-based surgery, those with non-metastatic lymph nodes and those who underwent lymphadenectomy had significantly higher survival rates. In patients who had RH-based surgery, survival rates at the 24m time point of those who did not add other treatments was higher than those who did, but for those who had total hysterectomy-based surgery, the addition of other treatments to prolong median survival may be considered. In the overall analysis, age and lymphadenectomy were associated with increased and reduced risk of death in these patients, respectively. Although there is no statistical difference, stage III&IV, TAH, lymphatic metastases increase the risk of death; whereas radical hysterectomy was associated with reduced risk of death. In the subgroup analysis, for patients who have undergone radical hysterectomy-based surgery, lymphadenectomy reduces the risk of death, while lymphatic metastases and complementary other treatments increase the risk of death. For patients who have undergone total hysterectomy-based surgery, complementary treatment reduces the risk of death. In conclusion, via summarizing previous reports, the recommended treatment procedure for PMMC are radical hysterectomy and lymphadenectomy. The addition of other treatment options for patients who undergoing RH-based surgery need further study.
... In melanoma, CEACAM1 is neo-expressed as normal melanocytes are negative for CEACAM1 [3]. CEACAM1 promotes melanoma cell growth [30] and metastasis [31], and CEACAM1positive tumors correlate with poor survival [32]. Importantly, the pro-tumorigenic effect is systematically associated with the long isoforms (CEACAM1-4L and 1-3 L) rather than the short ones. ...
Inhibitory receptors (IRs), such as the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), are cell surface molecules expressed on both normal epithelial, endothelial, and hematopoietic cells and on neoplastic cells. IRs are usually used by cancer cells to inhibit immune cell functions. Thus, CEACAM1 positive tumor cells can interact homophilically with CEACAM1 expressed on T and NK cells to inhibit their antibody-dependent cell-mediated cytotoxicity (ADCC). In this study, we investigated the effect of agonistic/activating anti-CEACAM1 monoclonal antibody (mAb) on melanoma cell lines in vitro and in vivo, following our hypothesis that activation of CEACAM1 on melanoma cells by distinct mAbs may induce inhibition of cancer cell proliferation and/or their death. To address this, we established an activating anti-CEACAM1 mAb (CCM5.01) and characterized its binding to the CEACAM1 receptor. Using this mAb, we assessed the expression of CEACAM1 on four different human melanoma cell lines by western blot and flow cytometry and determined its effect on cell viability in vitro by MTT assay. Furthermore, we evaluated the mAb mechanism of action and found that binding of CEACAM1 with CCM5.01 induced SHP1 phosphorylation and p53 activation resulting in melanoma cell apoptosis. For in vivo studies, a xenograft model of melanoma was performed by injection of Mel-14 cells subcutaneously (s.c.) in SCID/Beige mice followed by intraperitoneal (i.p.) injection of CCM5.01 or of IgG1 isotype control every other day. CCM5.01 treated mice showed a slight but not significant decrease in tumor weight in comparison to the control group. Based on the obtained data, we suggest that activating CEACAM1 on melanoma cells might be a promising novel approach to fight cancers expressing this IR.
... CEACAM1 is a widely expressed immunoglobulin cell adhesion factor that is involved in regulating cell proliferation, apoptosis, angiogenesis, and the immune response [37]. Previous studies have shown that CEACAM1 knockdown inhibits melanoma metastasis and is associated with a good survival rate [38]. Moreover, CEACAM1 knockout decreases cell adhesion, migration, and metastasis in colon cancer [39]. ...
It is well known that non-small cell lung cancer (NSCLC) is a malignant tumor with high incidence in the world. We aimed to clarify a possible target and identify its precise molecular biological mechanism in NSCLC. NLR family CARD domain containing 5 (NLRC5) is widely expressed in tissues and exerts a vital role in anti-tumor immunity. We determined NLRC5 expression by RT-qPCR and western blot assay. The role of NLRC5 in the development of NSCLC was assessed by a loss-of-function assay. CCK-8, Annexin-V-FITC/PI Apoptosis Detection Kit, Transwell, and wound healing assays were used to determine the cell functions. Drug resistance-related proteins were analyzed by western blot assay. Furthermore, the modulation of NLRC5 on carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression and subsequent PI3K/AKT signaling was assessed. In this study, a hyper-expression of NLRC5 was found in NSCLC tissues and cell lines. Knockdown of NLRC5 suppressed cell viability, invasion, and migration, and furthermore promoted cell apoptosis in NSCLC cells. Moreover, under normoxia or hypoxia treatment, the upregulation of NLRC5 was related to carboplatin resistance. NLRC5 silencing increased carboplatin-resistant cell chemosensitivity, as evidenced by the increase in the cell inhibition rate and decrease in drug resistance-related protein expression. Mechanistically, NLRC5 knockdown inhibited the expression of CEACAM1 and subsequently blocked the PI3K/AKT signaling pathway. In conclusion, NLRC5 promotes the malignant biological behaviors of NSCLC cells by activating the PI3K/AKT signaling pathway via the regulation of CEACAM1 expression under normoxia and hypoxia.
... Numerous studies have suggested that epithelial-to-mesenchymal transition (EMT) contributes to early-stage dissemination of cancer cells and is pivotal for invasion and metastasis of melanoma. 12,13 Matrix metalloproteinases (MMP2, MMP9) play vital roles in tissue remolding and cancer metastasis. 14 As shown in Figure 3(a), mesenchymal-related gene (N-cadherin and E-cadherin), invasion-and metastasis-related gene (MMP2 and MMP9) expression in melanoma cells were significantly decreased after Piezo1 inhibition compared with control group. ...
Melanoma is a highly aggressive cancer that can metastasize at early stage. The aim of this study is to clarify the role of Piezo1 and its potential mechanism in regulating the malignant phenotypes of melanoma. In the present study, we first showed that Piezo1 was abnormally expressed in melanoma, which accelerated the malignant progression by activating AKT/mTOR signaling. Firstly, we found that Piezo1 was upregulated in melanoma and associated with poor survival. Additionally, Piezo1 knockdown significantly weakened intracellular calcium signal and viability of melanoma cells. Furthermore, Piezo1 knockdown inhibited the transendothelial migration and invasion in vitro, as well as metastasis in vivo. Mechanistically, we found that Piezo1 activated AKT/mTOR signaling to maintain malignant phenotypes of melanoma. Therefore, Piezo1 acts as an oncogene in melanoma cells and provides a novel candidate for melanoma diagnosis and treatment.
... Specifically, it induced EMT, by regulating the transcription factor TWIST through the HRE located in the TWIST proximal promoter [75,76]. In accordance, altered TWIST expression was found to be correlated with shortened survival in patients with CM [77]. ...
Hypoxia, a condition of low oxygen availability, is a hallmark of tumour microenvironment and promotes cancer progression and resistance to therapy. Many studies reported the essential role of hypoxia in regulating invasiveness, angiogenesis, vasculogenic mimicry and response to therapy in melanoma. Melanoma is an aggressive cancer originating from melanocytes located in the skin (cutaneous melanoma), in the uveal tract of the eye (uveal melanoma) or in mucosal membranes (mucosal melanoma). These three subtypes of melanoma represent distinct neoplasms in terms of biology, epidemiology, aetiology, molecular profile and clinical features.
In this review, the latest progress in hypoxia-regulated pathways involved in the development and progression of all melanoma subtypes were discussed. We also summarized current knowledge on preclinical studies with drugs targeting Hypoxia-Inducible Factor-1, angiogenesis or vasculogenic mimicry. Finally, we described available evidence on clinical studies investigating the use of Hypoxia-Inducible Factor-1 inhibitors or antiangiogenic drugs, alone or in combination with other strategies, in metastatic and adjuvant settings of cutaneous, uveal and mucosal melanoma.
Hypoxia-Inducible Factor-independent pathways have been also reported to regulate melanoma progression, but this issue is beyond the scope of this review.
As evident from the numerous studies discussed in this review, the increasing knowledge of hypoxia-regulated pathways in melanoma progression and the promising results obtained from novel antiangiogenic therapies, could offer new perspectives in clinical practice in order to improve survival outcomes of melanoma patients.
... Melanoma is a type of aggressive malignant neoplasm that originates from the skin and mucosa with high mortality rates. 1 With the development of medical science, melanoma treatment has entered a phase of diversified treatment. However, the melanoma treatment remains a challenge because of its rarity and heterogeneity. 2 Therefore, it is an urgent need to look for novel therapeutic targets for melanoma. ...
Purpose
Melanoma is a serious and malignant disease worldwide. Seeking diagnostic markers and potential therapeutic targets is urgent for melanoma treatment. SOX10, a member of the SoxE family of genes, is a transcription factor which can regulate the transcription of a wide variety of genes in multiple cellular processes.
Methods
The mRNA level and protein expression of SOX10 is confirmed by bioinformatic analysis and IHC staining. MTT, clone formation and EdU analysis showed that SOX10 knockdown (KD) could significantly inhibit melanoma cell proliferation. FACS analysis showed that SOX10 KD could markedly enhance the level of cell apoptosis. The downstream target signaling pathway is predicted by RNA-seq based on the public GEO database. The activation of Notch signaling mediated by SOX10 is tested by qPCR and Western blot.
Results
Ectopic upregulation of SOX10 was found in melanoma patient tissues compared to normal nevus tissues in mRNA and protein levels. Furthermore, both mRNA and protein level of SOX10 were negatively correlated with melanoma patient’s prognosis. SOX10 knockdown could obviously suppress the proliferation ability of melanoma cells by inactivating Notch signaling pathway.
Conclusion
Our study confirmed that SOX10 is an oncogene and activate Notch signaling pathway, which suggests the potential treatment for melanoma patients by target SOX10/Notch axis.
... However, P21 and PTEN, classical tumour suppressors were increased (Fig. 3a). Numerous studies have suggested that epithelial-to-mesenchymal transition (EMT) contributes to early-stage dissemination of cancer cells and is pivotal for invasion and metastasis of melanoma [13,14]. In addition, matrix metalloproteinases (MMP2, MMP9) play vital roles in tissue remolding and cancer metastasis [15]. ...
Background: Melanoma is a highly aggressive cancer that can metastasize at early stage. The mechanosensitive ion channel Piezo1 plays a crucial role in embryonic development, tumour growth, migration, invasion and vascularization. The aim of this study was to clarify the role of Piezo1 and its potential mechanism in regulating the malignant phenotypes of melanoma.
Methods: The expression of Piezo1 in melanoma was analysed using quantitative real-time PCR and public databases. The effect of Piezo1 on cell viability was examined using a cell counting kit-8 assay. Cell invasion and migration ability were assessed using wound healing assays, transwell assays, transendothelial migration assays and a tail vein cancer metastasis model in vivo. Bioinformatics and western blot assayses were used to explore the effect of Pieoz1 on P13K/AKT signalling.
Results: Piezo1 was upregulated in melanoma and was positively associated with poor survival. Piezo1 knockdown significantly weakened the intracellular calcium signal significantly and inhibited the viability of melanoma cells. Furthermore, Piezo1 knockdown inhibited the invasion and metastasis ability in vitro and in vivo by inducing the expression of cell cycle, invasion and metastasis related genes. To clarify the possible mechanism, it seems that Piezo1 activates the PI3K-AKT signalling to maintain malignant phenotypes of melanoma.
Conclusion: Piezo1 acts as an oncogene in melanoma cells and provides a novel candidate for melanoma diagnosis and treatment.
