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Abstract-CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1␤, IL-6, tumor necrosis factor-␣, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-␥ is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR-␥ gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP-␦ plays a pivotal role in transactivation of PPAR-␥ gene. It has been well known that the interaction between C/EBPs and PPAR-␥ plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR-␥ and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP-␦ expression induced by inflammation positively regulated transcription and protein expression of PPAR-␥ in vascular smooth muscle cells (VSMCs). On the other hand, PPAR-␥ ligands troglitazone, pioglitazone, and 15-deoxy-⌬ 12,14 -prostaglandin J 2 inhibited IL-1␤-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR-␥ ligands inhibited IL-1␤-induced transactivation of IL-6 gene via suppression of not only nuclear factor-B but also C/EBP-DNA binding. Moreover, PPAR-␥ ligands suppressed protein expression and transcription of C/EBP-␦ through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-␦ is negatively autoregulated via transactivation of PPAR-␥. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.

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Oral squamous cell carcinoma (OSCC) has a high incidence of cervical micrometastases and sometimes metastasizes contralaterally because of the rich lymphatic intercommunications relative to submucosal plexus of oral cavity that freely communicate across the midline, and it can facilitate the spread of neoplastic cells to any area of the neck consequently. Clinical and histopathologic factors continue to provide predictive information to contralateral neck metastases (CLNM) in OSCC, which determine prophylactic and adjuvant treatments for an individual patient. This review describes the predictive value of clinical-histopathologic factors, which relate to primary tumor and cervical lymph nodes, and surgical dissection and adjuvant treatments. In addition, the indications for elective contralateral neck dissection and adjuvant radiotherapy (aRT) and strategies for follow-up are offered, which is strongly focused by clinicians to prevent later CLNM and poor prognosis subsequently.

Hepatocellular carcinoma (HCC) is one of the most malignant human tumours because of its high incidence of metastasis. The mechanisms underlying the metastasis of HCC, however, remain poorly understood. In this study, we performed cDNA microarray analysis to profile gene expression patterns in two subtypes of HCC, solitary large HCC (SLHCC) and nodular HCC (NHCC), which differ significantly in the incidence of metastasis. Among 668 genes that were differentially expressed, we focused on RhoC, whose expression was significantly decreased in SLHCC compared to NHCC. The expression of RhoC in HCC and pericarcinomatous liver tissues (PCLT) was analysed at both the mRNA and protein levels by reverse transcription -polymerase chain reaction (RT -PCR) and Western blotting. In addition, immunohistochemistry was also performed on 94 cases of HCC with follow-up information. Collectively, our data indicate that the expression of RhoC significantly increased in HCC compared to PCLT; extrahepatic metastatic lesions expressed significantly higher levels of RhoC than the corresponding intrahepatic HCC tissues. There is a highly significant correlation of the RhoC expression levels with tumour vein invasion, number of tumour nodes and the status of differentiation. Significantly, the HCC patients with RhoC-positive expression had shorter survival than those with RhoC-negative expression. Together, our findings suggest a strong correlation between the expression of RhoC and HCC metastasis, implicating RhoC as a potential prognosis marker and therapeutic target for HCC.

Lung cancer is a major public health problem worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases. Autophagy has recently sparked great interest, and it is thought to participate in a variety of diseases, including lung cancer. Uncoordinated (Unc) 51-like kinase 1 (Ulk1), a serine/threonine kinase, plays a central role in the autophagy pathway. However, the role of Ulk1 in NSCLC remains unclear. We report that NSCLC cell lines exhibited high expression of Ulk1 and that Ulk1 was negatively correlated with prognosis in lung cancer patients. Knockdown of Ulk1 or the inhibition of Ulk1 by the selective inhibitor SBI0206965, inhibited cell proliferation, induced cell apoptosis and enhanced the sensitivity of cisplatin against NSCLC cells. Moreover, we demonstrated that Ulk1 exerted oncogenic activity in NSCLC by modulating both autophagy and apoptosis pathways. Inhibition of autophagy by SBI0206965 sensitized NSCLC cells to cisplatin by inhibiting cisplatin induced cell-protective autophagy to promote apoptosis. Furthermore, SBI0206965 promoted apoptosis in NSCLC cells independent of autophagy, which was partly mediated by destabilization of Bcl2/Bclxl. In summary, our results show that inhibition of Ulk1 suppresses NSCLC cell growth and sensitizes NSCLC cells to cisplatin by modulating both autophagy and apoptosis pathways, and that Ulk1 might be a promising target for NSCLC treatment.

SUMMARY Radial glial progenitors (RGPs) represent the major neural progenitors for generating neurons and glia in the developing mammalian cerebral cortex 1 - 3 . They position their centrosomes away from the nucleus at the ventricular zone surface 4 - 7 . However, the molecular basis and precise function of this highly unique and characteristic subcellular organization of the centrosome remain largely unknown. Here we show that apical membrane anchoring of the centrosome controls the mechanical properties of mouse cortical RGPs and consequently their mitotic behaviour and cortical size and formation. Mother centriole in RGPs specifically develops distal appendages to anchor to the apical membrane. Selective removal of Centrosomal protein 83 (CEP83) eliminates mother centriole distal appendages and disrupts centrosome apical membrane anchorage, resulting in microtubule disorganization and apical membrane stretching and stiffening. It activates mechanically-sensitive Yes-associated protein (YAP) and promotes excessive RGP proliferation and subsequent intermediate progenitor overproduction, leading to the formation of an enlarged cortex with abnormal folding. Simultaneous elimination of YAP suppresses cortical enlargement and folding caused by CEP83 removal. Together, these results uncover a previously unknown role of the centrosome in regulating the mechanical features of neural progenitors, and the size and configuration of the mammalian cerebral cortex.

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