Selinexor assists vorinostat in inhibiting HDAC activity via promoting the accumulation of maspin in the nucleus of oral tongue squamous cell carcinoma cells.

Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cancer with a low overall survival rate, necessitating effective treatments. This study reports the anti-OTSCC effect of vorinostat and selinexor. OTSCC cell lines SCC-4 and SCC-25 were cultured to determine the effects of vorinostat and/or selinexor on cell survival, invasion, migration, and apoptosis. The transplanted tumor model of SCC-25 in nude mice was established to observe the therapeutic effects of vorinostat and/or selinexor. Western blotting was used to determine protein expressions in tumor cells. The results showed that histone deacetylase 1 (HDAC1) and exportin 1 (XPO1) were highly expressed, while nuclear maspin was expressed at a low rate in SCC-4 and SCC-25 compared to the normal tongue tissue. In vitro, both vorinostat and selinexor effectively inhibited cell viability, invasion, and migration, promoted cell apoptosis, down-regulated HDAC1, Matrix Metalloproteinase 2 (MMP2), and B cell leukemia/lymphoma 2 (Bcl-2), and up-regulated nuclear maspin and cleaved caspase 3. In vivo, both vorinostat and selinexor inhibited the growth of SCC-25-bearing tumors, down-regulated the expression of Ki67, HDAC1, MMP2, and Bcl-2, and promoted the expression of nuclear maspin and cleaved caspase 3. The combination of these two drugs exhibited synergistic effects both in vivo and in vitro. Our evidence shows that vorinostat combined with selinexor is an effective treatment for OTSCC. The mechanism may be that selinexor promotes the accumulation of maspin in the nucleus, an endogenous HDAC1 inhibitory protein to inhibit the HDAC1 activity of vorinostat and exert a synergistic anti-OTSCC effect.

miR-195-5p regulates cell proliferation, apoptosis, and invasion of thyroid cancer by targeting telomerase reverse transcriptase.

In most human primary cancers, the expression, or telomerase activity, of telomerase reverse transcriptase (TERT) is detectable. However, the mechanism ofTERTactivity within oncogenesis of thyroid cancer remains largely unknown. In this study, we identified miR-195-5p as having involvement in cell proliferation, apoptosis, and invasion in human thyroid cancer. MTT was used to measure cell proliferation, Transwell chamber was used to measure invasion. Western blotting was used to detect the expressions of TERT, PCNA, and Ki67. Target gene prediction software predicted that TERT may be the target gene of miR-195-5p. Luciferase reporting system was used to identify the targeting relationship. A significant increase of in TERT expression was observed by immunohistochemistry compared with normal tissue, however, a decrease in miR-195-5p expression using qRT-PCRand western blot compared with normal cells. Functional analysis demonstrates that miR-195-5p negatively correlated withTERTand inhibitedTERTexpression through its interaction with theTERT3'-untranslatedregion (3'-UTR). Overexpression of miR-195-5p was shown to inhibit proliferation and invasion, and promote apoptosis of CAL-62 thyroid cancer cells. miR-195-5p-mediatedeffects were rescued by the overexpression ofTERT. Altogether, our data demonstrate that miR-195-5p regulates cell proliferation, apoptosis, and invasion in human thyroid cancer viaTERT, providing evidence of a new potential therapeutic target for further investigation.

Integrated tissue proteome and metabolome reveal key elements and regulatory pathways in cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (CSCC) is a widespread malignancy but has a very low long-term survival rate for patients at the metastatic stage. Therefore, it is urgent to identify prognostic biomarkers for CSCC and improve our understanding of disease progression. Here we took advantage of a data-independent acquisition (DIA)-based nano liquid chromatography equipped with an orbitrap mass spectrometry (nLC-MS/MS) and ultraperformance LC coupled to a time-of-flight tandem MS (UPLC-TOF-MS/MS) technique to analyze cancer and corresponding noncancerous tissues from 20 CSCC patients for integrated proteomic and metabolomic analyses. Overall, 6241 tissue proteins were detected, while 136 proteins were significantly expressed in CSCC tissues. Further functional analysis revealed that various biological processes were highly enriched and participated in the pathogenesis of CSCC, especially DNA damage responses. Moreover, 641 named metabolites in total were identified, among which 181 were significantly changed in CSCC tissues. A total of 101 pathways were significantly enriched including apoptosis, autophagy, PI3K-Akt and mTOR signaling pathways. Interestingly, two pathways, protein digestion & absorption and platelet activation were both enriched in proteomic and metabolomic studies involving 5 proteins and 11 metabolites. Accordingly, a four-metabolite panel consisting of arachidonate, glutamine, glutamic acid, and proline (all area under the curve (AUC) values more than 0.9) was developed with a high accuracy (0.971) to distinguish the 20 detected cancer tissues from their noncancerous tissues. Collectively, our work highlighted the key elements and regulatory pathways involved in the pathogenesis of CSCC. More importantly, the present study not only provided potential biomarkers for the early diagnosis of CSCC, but also expanded our knowledge of the physiopathology of the disease. SIGNIFICANCE: CSCC is the second most common human cancer but has few treatment options and few sensitive biomarkers for diagnosis. Here we comprehensively revealed its molecular characteristics by performing integrated tissue proteomic and metabolomic analyses. Significantly distinct profiles and certain enriched pathways including DNA damage responses were identified as associated with CSCC. Moreover, protein digestion & absorption and platelet activation were both enriched in the proteome and metabolome. These identified molecular changes probably play significant roles in CSCC development. Finally, we developed a four-metabolite panel to distinguish CSCC with high accuracy. Overall, our data not only provided potential diagnostic biomarkers, but also extended knowledge on the pathogenesis of CSCC.

Long non-coding RNA PHACTR2-AS1 promotes tongue squamous cell carcinoma metastasis by regulating Snail.

Long non-coding RNA is an endogenous non-coding RNA that has currently been proved to be an important player in cancer cell biology. In the present study, we investigated the biological role of PHACTR2-AS1 in tongue squamous cell carcinoma (TSCC). PHACTR2-AS1 was preferentially localized in the cytoplasm, and was notably upregulated in TSCC tissues. High PHACTR2-AS1 was correlated with tumour differentiation, metastatic clinical features, relapse and shortened survival time. Depletion of PHACTR2-AS1 did not affect TSCC cell viability and colony formation ability, whereas substantially inhibited cell migration and invasion in vitro and lung metastasis in vivo. Mechanistically, PHACTR2-AS1 could sponge miR-137 to increase Snail expression, resulting in triggering epithelial-mesenchymal transition process, thereby promoting TSCC cell metastasis. Taken together, our data for the first time elucidate the metastasis-promoting role of PHACTR2-AS1 in TSCC, hinting a new therapeutic target for metastatic TSCC patients.