Effect of Hsa-miRNA-203a-3p on proliferation of skin squamous cell carcinoma-1 human skin squamous cell cancer cells by targeting adenomatous polyposis coli using magnetic nanoparticles

To investigate the effect of hsa-miR-203a-3p overexpression on the proliferation of human skin squamous cell carcinoma (CSCC) cells and its possible mechanism. Real-time PCR (RT-PCR) was used to detect the expression of miR-203a-3p in cell lines and clinical human CSCC samples. A luciferase reporter system was used to verify the targeted regulatory relationship of miR-203a-3p to APC, and a miR-203a-3p lentivirus overexpression vector was constructed and used to transfect CSCC SCL-1 cells. RT-PCR was used to detect changes in miR-203a-3p and APC gene expression and Western blot was used to detect differences in APC and β-catenin protein expression. MTT and clonogenic assays were used to evaluate cell growth and detect clone formation, respectively. MiR-203a-3p showed decreased expression in SCL-1 cells and CSCC samples. Results of luciferase reporter assay showed that the ratio of Renilla luciferase to Firefly luciferase was significantly decreased in SCL-1 cells of the APC 3′-UTR+miR-203a-3p (wild-type) group compared with those of the APC 3′-UTR+negative control group. After lentiviral infection of SCL-1 cells, the abundance of miR-203a-3p and phosphorylated β-catenin protein was significantly increased, whereas the abundance of APC and β-catenin protein was significantly reduced. Cell phenotyping analysis showed that miR-203a-3p decreased cell proliferation. MiR-203a-3p inhibits the proliferation of SCL-1 cells through targeted regulation of APC and may play a role as a tumor suppressor gene through the Wnt pathway. Nanotechnology has potential future research applications in gene vector transfection technology.

484 Preliminary efficacy of the IL-15 superagonist SO-C101 in combination with pembrolizumab in patients with advanced/metastatic solid tumors

BackgroundSO-C101 (IL 15/IL-15Rα sushi + domain fusion protein) was investigated in a multicenter, open-label, dose escalation study as monotherapy and in combination with pembrolizumab in patients with selected advanced/metastatic tumors (NCT04234113). Synergistic effects of SO-C101 and an anti-programmed cell death protein 1 (PD-1) antibody have been validated in various tumor mouse models inducing a protective memory response.MethodsThe combination part of the study follows a classical 3+3 dose escalation design. Study objectives are to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). The evaluation period for dose-limiting toxicities in each dose step is 21 days. The RP2D is defined as MTD or a dose below, taking into consideration pharmacokinetic and pharmacodynamic parameters.The study is ongoing (data cut-off 21 June 2021).ResultsA total of 12 patients with a median of 2 (range 1–6) lines of previous systemic therapies were treated at SO-C101 dose levels 1.5 µg/kg (3 patients), 3.0 µg/kg (3 patients), and 6.0 µg/kg (6 patients) together with 200 mg of pembrolizumab. One dose-limiting toxicity of grade (G) 3 cytokine release syndrome (CRS) was observed in one patient at 6.0 µg/kg. The MTD has not yet been reached.Of the treated patients, 2 had long-term stable disease (anal squamous cell carcinoma patient at 1.5 µg/kg, duration 25 weeks; gastric carcinoma patient at 3.0 µg/kg, duration 14 weeks) and 3 achieved a partial response (thyroid gland cancer patient at 3.0 µg/kg, target lesion decrease by 36%; skin squamous cell carcinoma patient at 6.0 µg/kg, target lesion decrease by 40%; and melanoma patient at 6.0 µg/kg, target lesion decrease by 58%). The patients with skin squamous cell carcinoma and melanoma had previously progressed on anti-PD-1 therapy, while the patient with thyroid cancer was anti-PD-1 naïve.The most common study drug-related adverse events were lymphopenia, local injection site reactions, transaminase increase, fever, chills as well as CRS-related symptoms (all mainly G1 or G2 and resolved). The only study drug-related adverse event >G2 that occurred in more than one patient was lymphopenia. No treatment-related death was reported.ConclusionsAlthough the MTD of SO-C101 in combination with pembrolizumab has not been reached yet, clinical efficacy signals were already observed in 5 patients. Available safety data indicate good tolerability. SO-C101 in combination with pembrolizumab has already shown the potential to provide an additional clinical benefit to patients with solid tumors.Trial RegistrationNCT04234113Ethics ApprovalThis study was approved by the FDA (IND 140011) and by the Ethics Boards of participating institutions

Sorafenib-related generalized eruptive keratoacanthomas (Grzybowski syndrome): a case report

Background Sorafenib is an oral multikinase inhibitor that targets Raf serine/threonine receptor tyrosine kinases and inhibits tumor cell growth and angiogenesis. Cutaneous toxicities of sorafenib are common, including cutaneous eruptions (such as truncal erythema and seborrheic-dermatitis-like changes) and hand–foot syndrome. Keratoacanthomas and squamous cell carcinomas have been reported previously; however, we report a case of multiple eruptive keratoacanthomas in the form of Grzybowski syndrome after initiation of sorafenib. Case presentation We report a 63-year-old Caucasian male who developed multiple cutaneous eruptive keratoacanthomas after starting sorafenib 400 mg twice daily. He had a known history of hepatitis-C-related cirrhosis and hepatocellular carcinoma, and previously had actinic keratosis and skin squamous cell carcinoma excision. Approximately two and a half months after starting sorafenib, the patient initially developed two lesions, one on each forearm, and after excision, these lesions demonstrated histological features of squamous cell carcinoma. One month later, the patient presented with approximately 48 new skin lesions of varying size on the back, bilateral upper limbs, and face requiring excisional biopsy of a large number of these lesions. Histopathology showed eruptive invasive keratoacanthomas (Grzybowski syndrome). Sorafenib was temporarily stopped and subsequently restarted at a lower dose. Acitretin 25 mg daily was commenced after few weeks, and no further keratoacanthomas developed during his treatment. Conclusions We report a unique case of sorafenib-associated Grzybowski syndrome. Temporary interruption and dose reduction of sorafenib and use of acitretin appeared to prevent further development of keratoacanthomas.

Connexin26 Modulates the Radiosensitivity of Cutaneous Squamous Cell Carcinoma by Regulating the Activation of the MAPK/NF-κB Signaling Pathway

Previous studies have confirmed that the gap junction protein Connexin26 (Cx26) is specifically expressed in human skin tissue. Cx26 can transmit radiation-induced damage signals. However, no study has yet reported whether Cx26 expression affects the radiosensitivity of human skin squamous cancer cells or the mechanism by which this occurs. In this study, we found that human skin squamous cell carcinoma cells (A431 cells) expressed significantly more Cx26 and were more sensitive to radiation compared to normal human keratinocytes (HaCaT cells). Knockdown of Cx26 in A431 cells (A431Cx26–/–) decreased radiosensitivity relative to control cells and altered the expression of key proteins in the MAPK and NF-κB signaling pathways. These results demonstrate that Cx26 expression might play an important role in mediating radiation damage in A431 cells and could serve as a potential target for clinical radiotherapy for cutaneous squamous cell carcinoma.

MBNL1 Suppressed Cancer Metastatic of Skin Squamous Cell Carcinoma Via by TIAL1/MYOD1/Caspase-9/3 Signaling Pathways

Objective: The incidence of skin squamous cell carcinoma (SSCC) has recently been increasing, with diverse clinical manifestations.SSCC could metastasize to lymph nodes or other organs, posing a great threat to life. The present study was designed to investigate the function and underlying mechanism of muscleblind-like protein 1 (MBNL1) in skin squamous cell carcinoma. Methods: SCL-1 cell was used for vitro model and transfected with MBNL1 or siMBNL1 plasmids. MTT Assays, LDH activity ELISA, and Transwell chamber migration experiment were used to confirm the effects of MBNL1 on cell growth of SCL-1 cell. Western blot analysis was used to analyze the mechanism of MBNL1 in SCL-1 cell. Results: Down-regulation of MBNL1 promoted cell metastasis of SSCC, while up-regulation of MBNL1 reduced cell metastasis of SSCC in vitro. Down-regulation of MBNL1 suppressed the protein expression of T cell intracellular antigen (TIAL1), myogenic determinant 1 (MyoD1) and Caspase-3 in vitro. Consistent with these observations, inhibition of TIAL1 or MYOD1 expression attenuated the effects of MBNL1 in SSCC. Conclusion: The present study revealed that MBNL1 suppressed thecancer metastatic capacity of SSCC via by TIAL1/MYOD1/Caspase-3 signaling pathways.