The role of a YAP-IGF-1R signaling loop in HCC resistance to sorafenib remains unknown. Method: Sorafenib-resistant cells were generated by treating naïve cells (HepG2215 and Hep3B) with sorafenib. Different cancer cell lines from databases were analyzed through the ONCOMINE web server. BIOSTORM–LIHC patient tissues (46 nonresponders and 21 responders to sorafenib) were used to compare YAP mRNA levels. The HepG2215_R-derived xenograft in SCID mice was used as an in vivo model. HCC tissues from a patient with sorafenib failure were used to examine differences in YAP and IGF-R signaling. Results: Positive associations exist among the levels of YAP, IGF-1R, and EMT markers in HCC tissues and the levels of these proteins increased with sorafenib failure, with a trend of tumor-margin distribution in vivo. Blocking YAP downregulated IGF-1R signaling-related proteins, while IGF-1/2 treatment enhanced the nuclear translocation of YAP in HCC cells through PI3K-mTOR regulation. The combination of YAP-specific inhibitor verteporfin (VP) and sorafenib effectively decreased cell viability in a synergistic manner, evidenced by the combination index (CI). Conclusion: A YAP-IGF-1R signaling loop may play a role in HCC sorafenib resistance and could provide novel potential targets for combination therapy with sorafenib to overcome drug resistance in HCC.

The epidermal differentiation complex (EDC) encodes a group of unique proteins expressed in late epidermal differentiation. The EDC gave integuments new physicochemical properties and is critical in evolution. Recently, we showed β-keratins, members of the EDC, undergo gene cluster switching with overexpression of SATB2 (Special AT-rich binding protein-2), considered a chromatin regulator. We wondered whether this unique regulatory mechanism is specific to β-keratins or may be derived from and common to EDC members. Here we explore (1) the systematic expression patterns of non-β-keratin EDC genes and their preferential expression in different skin appendages during development, (2) whether the expression of non-β-keratin EDC sub-clusters are also regulated in clusters by SATB2. We analyzed bulk RNA-seq and ChIP-seq data and also evaluated the disrupted expression patterns caused by overexpressing SATB2. The results show that the expression of whole EDDA and EDQM sub-clusters are possibly mediated by enhancers in E14-feathers. Overexpressing SATB2 down-regulates the enriched EDCRP sub-cluster in feathers and the EDCH sub-cluster in beaks. These results reveal the potential of complex epigenetic regulation activities within the avian EDC, implying transcriptional regulation of EDC members acting at the gene and/or gene cluster level in a temporal and skin regional-specific fashion, which may contribute to the evolution of diverse avian integuments.

Feathers, the primary skin appendage covering the avian body, undergo dynamic phenotypic changes throughout a bird’s life. Males and females of the same species can exhibit sexually dichromatic plumage colors which play a critical role in mating choice, survival, and ecological interactions. In this study, we investigate the molecular mechanisms underlying the changes of color that occur during the transition from juvenile to adult feathers, known as the secondary transition. We focus on sexual dichromatism of craniofacial plumage and use the male cheek domain of the zebra finch (Taeniopygia guttata) as the major model. The transcriptome of the cheek and scalp (crown) domains in males and females of wild-type and genetic color variants were compared. We found that (1) Craniofacial color patterning operates through two regulatory layers. The first layer involves transcription factor (TF) genes that define the cheek domain such as PITX1, PAX1, PAX6. The second layer comprises pigment-related genes responsible for specific colors, including male-biased TFs (SOX10 and DMRT1) and transporters associated with red pigment synthesis. (2) Surprisingly, ASIP, which controls pheomelanin production in other species, was expressed in both male (red) and female (gray) cheeks. Instead, PAX1 in cheek dermal fibroblasts may serve as an upstream regulator, potentially triggering the male-biased color pattern through PAX6 and SOX10. PAX6 and SOX10 in melanocytes potentially enhance the expression of GPR143, SLC45A2, and TMEM163, driving increased pheomelanin production in males. (3) Sexual dichromatism is associated with sex-linked genes on the Z chromosome, notably SLC45A2. In addition, motif analysis comparing the binding strength between regional transcription factors and melanogenesis genes suggests that craniofacial pigmentation may have evolved convergently in passerine birds. These findings provide novel insights into the molecular control of color patterning and lay the groundwork for further studies on avian sexual dichromatism and secondary feather transition.

Targeting the distribution of germ-cell markers is a widely used strategy for investigating germline development in animals. Among these markers, the vasa (vas) orthologues, which encode ATP-dependent RNA helicases, are highly conserved. Previous studies have examined asexual (parthenogenetic) and viviparous embryos of the pea aphid Acyrthosiphon pisum using a cross-reacting Vas antibody. This study utilized a specific antibody against Ap-Vas1, a Vas orthologue in the pea aphid, to gain new insights into germline development. The Ap-Vas1-specific antibody facilitates earlier detection of germ-plasm assembly at the oocyte posterior, challenging the previous assumption that germ-plasm assembly begins only at the onset of embryogenesis. Treatment of oocytes and early embryos with cytoskeleton inhibitors suggests that germ-plasm assembly primarily depends on actin, in contrast to the fly Drosophila melanogaster, where both actin and microtubules are essential. Since pea aphids lack an orthologue of osk, which encodes the protein Osk responsible for anchoring Vas to the germ plasm in Drosophila, this suggests that pea aphids employ distinct mechanisms for osk- and microtubule-independent formation of the germ plasm. Moreover, the clustering of germ cells into germarium-like structures in the extraembryonic region before entering the embryos suggests a gonad formation process different from that in Drosophila, where germ cells begin to cluster into germaria after settling within the embryonic gonads. Therefore, the analysis of the Ap-Vas1 distribution provides a deeper understanding of germline development in asexual pea aphids, uncovering novel aspects of parthenogenetic and viviparous reproduction in insects.