SOX genes encode a family of high-mobility group transcription factors that play critical roles in organogenesis. The functional specificity of different SOX proteins and the tissue specificity of a particular SOX factor are largely determined by the differential partnership of SOX transcription factors with other transcription regulators, many of which have not yet been discovered. Virtually all members of the SOX family have been found to be deregulated in a wide variety of tumors. However, little is known about the cellular and molecular behaviors involved in the oncogenic potential of SOX proteins. Using cell culture experiments, tissue analysis, molecular profiling, and animal studies, we report here that SOX2 promotes cell proliferation and tumorigenesis by facilitating the G 1 /S transition and through its transcription regulation of the CCND1 gene in breast cancer cells. In addition, we identified ␤-catenin as the transcription partner for SOX2 and demonstrated that SOX2 and ␤-catenin act in synergy in the transcription regulation of CCND1 in breast cancer cells. Our experiments not only determined a role for SOX2 in mammary tumorigenesis but also revealed another activity of the multifunctional protein, ␤-catenin.The SOX 2 gene family encodes a group of transcription factors that are characterized by a highly conserved high-mobility group (HMG) domain (1-3). These genes are found throughout the animal kingdom, are expressed in a restricted spatial-temporal pattern, and play critical roles in stem cell biology, organogenesis, and animal development (3, 4). For example, overexpression of Sox2 in mouse neural stem cells blocks their differentiation, and inhibition of Sox2 in these cells causes their premature exit from the cell cycle and differentiation into neurons(5). Depletion of Sox2 by RNA interference blocks the proliferation of neural stem-like cells and causes them to differentiate into neurons(6).Recently, a number of links have been found between SOX transcription factors and human cancers (7). For instance, SOX2 has been found to be an immunogenic antigen in 41% of small cell lung cancer patients (8) and in 29% of meningioma patients (9). Immunohistochemistry results suggest that SOX2 is involved in later events of carcinogenesis, such as invasion and metastasis of pancreatic intraepithelial neoplasia (10). SOX2 may also be involved in gastric carcinogenesis (11) and may be amplified in prostate cancers (12). Furthermore, SOX2 expression has been observed in 43% of basal cell-like breast carcinomas and was found to be strongly correlated with CK5/6, EGFR, and vimentin immunoreactivity, suggesting that SOX2 may play a role in conferring a less differentiated phenotype in these tumors (13).How SOX2 exerts its oncogenic potential is currently unknown. SOX proteins including SOX2 bind to specific DNA sequences (C(T/A)TTG(T/A)(T/A)) by means of their HMG domains in functioning as transcription factors to activate or repress target gene expression (2, 3). It is currently accepted that SOX proteins the...

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Organisms' life cycles consist of hierarchical stages, from a single phenological stage (for example, flowering within a season), to vegetative and reproductive phases, to the total lifespan of the individual. Yet phenological events are typically studied in isolation, limiting our understanding of life history responses to climate change. Here, we reciprocally transfer plant communities along an elevation gradient to investigate plastic changes in the duration of sequential phenological events for six alpine species. We show that prolonged flowering leads to longer reproductive phases and activity periods when plants are moved to warmer locations. In contrast, shorter post-fruiting leaf and flowering stages led to shorter vegetative and reproductive phases, respectively, which resulted in shorter activity periods when plants were moved to cooler conditions. Therefore, phenological responses to warming and cooling do not simply mirror one another in the opposite direction, and low temperature may limit reproductive allocation in the alpine region.

It has been confirmed that the systemic inflammation response index (SIRI) based on peripheral blood neutrophil, monocyte and lymphocyte counts can be used for the prognostication of patients with various malignant tumors. However, the prognostic value of SIRI in cervical cancer patients has not yet been reported. This study found that a higher SIRI was related to lymphovascular invasion and was also significantly associated with FIGO stage, radiotherapy, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR) but not related to other clinical and pathological parameters. According to the Kaplan-Meier survival analysis, a high SIRI was associated with the poor prognosis of cervical cancer patients in the primary and validation groups. SIRI, NLR, PLR, and MLR can all be used to determine the prognosis of patients with operable cervical cancer. Moreover, it was confirmed that only SIRI was an independent prognostic factor for patients with operable cervical cancer. The same result was obtained in the propensity score matching (PSM) analysis. In the ROC curve analysis, SIRI was more accurate in predicting the prognosis of cervical cancer patients. Then, a nomogram was established based on SIRI, FIGO stage and lymphovascular invasion, which could determine the prognosis of cervical cancer patients more accurately than FIGO stage. The validation cohort showed the same results. In addition, the changes in SIRI relative to the baseline value at 4-8 weeks after surgery were closely related to the survival of cervical cancer patients. Compared with those with unchanged SIRI (absolute value of variation <25%), cervical cancer patients with an increase in SIRI > 75% had worse OS (P < 0.001), while patients with a decrease in SIRI > 75% had a better prognosis (P < 0.001). SIRI can serve as a new independent prognostic index and a potential marker for therapeutic response monitoring in patients with curable cervical cancer. Compared with the traditional FIGO staging system, the nomogram integrating SIRI can predict the survival of cervical cancer patients more objectively and reliably after radical surgery.

Epithelial-to-mesenchymal transition (EMT) facilitates the escape of pancreatic cancer cells from the primary tumor site, which is a key early event in metastasis. In the present study, we examined if intermittent hypoxia facilitates the invasiveness of human pancreatic cancer cell lines (Panc-1 and BxPC-3) by Transwell assay. We used western blotting and flow cytometry analysis to quantify stem-like cells in the migratory cells during intermittent hypoxia in the human pancreatic cancer cells. Under normoxia or intermittent hypoxia, the expression of autophagy-related proteins (LC3-II and Beclin), hypoxia-inducible factor-1α (HIF-1α) and EMT-related markers (E-cadherin, Vimentin and N-cadherin) was examined by western blotting. siRNA and the autophagic inhibitor were used to access the role of HIF-1α and autophagy in promoting metastasis and EMT. Under intermittent hypoxia, pancreatic cancer cells demonstrated enhanced invasive ability and enriched stem-like cells. The migratory cells displayed stem-like cell characteristics and elevated the expression of LC3-II and Beclin-1, HIF-1α, E-cadherin, Vimentin and N-cadherin under intermittent hypoxia conditions. Moreover, enhanced autophagy was induced by the elevated level of HIF-1α. The metastatic ability and EMT of pancreatic cancer stem cells was associated with HIF-1α and autophagy. This novel finding may indicate the specific role of HIF-1α and autophagy in promoting the metastatic ability of pancreatic cancer stem cells. Additionally, it emphasizes the importance of developing therapeutic strategies targeting cancer stem cells and autophagy to reduce metastasis.

N-(5-Chloro-2,4-dihydroxyphenyl)-1-phenylcyclobutanecarboxamide (N-CDPCB, 1a) is found to be an inhibitor of the fat mass and obesity associated protein (FTO). The crystal structure of human FTO with 1a reveals a novel binding site for the FTO inhibitor and defines the molecular basis for recognition by FTO of the inhibitor. The identification of the new binding site offers new opportunities for further development of selective and potent inhibitors of FTO, which is expected to provide information concerning novel therapeutic targets for treatment of obesity or obesity-associated diseases.

RNA N6-methyladenosine (m6A) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA m6A is regulated by the RNA m6A methyltransferases methyltransferase-like 3 (METTL3), METTL14, and METTL16 (writers), demethylases FTO and ALKBH5 (erasers), and binding proteins YTHDC1–2, YTHDF1–3, IGF2BP1–3, and SND1 (readers). These RNA m6A modification proteins are frequently upregulated or downregulated in human cancer tissues and are often associated with poor patient prognosis. By modulating pre-mRNA splicing, mRNA nuclear export, decay, stability, and translation of oncogenic and tumor suppressive transcripts, RNA m6A modification proteins regulate cancer cell proliferation, survival, migration, invasion, tumor initiation, progression, metastasis, and sensitivity to anticancer therapies. Importantly, small-molecule activators of METTL3, as well as inhibitors of METTL3, FTO, ALKBH5, and IGF2BP1 have recently been identified and have shown considerable anticancer effects when administered alone or in combination with other anticancer agents, both in vitro and in mouse models of human cancers. Future compound screening and design of more potent and selective RNA m6A modification protein inhibitors and activators are expected to provide novel anticancer agents, appropriate for clinical trials in patients with cancer tissues harboring aberrant RNA m6A modification protein expression or RNA m6A modification protein–induced resistance to cancer therapy.