Tamoxifen remains the most effective treatment for estrogen receptor α (ERα)‐positive breast cancer. However, many patients still develop resistance to tamoxifen in association with metastatic recurrence, which presents a tremendous clinical challenge. To better understand tamoxifen resistance from the perspective of the tumor microenvironment, the whole microenvironment landscape is charted by single‐cell RNA sequencing and a new cancer‐associated fibroblast (CAF) subset, CD63 + CAFs, is identified that promotes tamoxifen resistance in breast cancer. Furthermore, it is discovered that CD63 + CAFs secrete exosomes rich in miR‐22, which can bind its targets, ER α and PTEN, to confer tamoxifen resistance on breast cancer cells. Additionally, it is found that the packaging of miR‐22 into CD63 + CAF‐derived exosomes is mediated by SFRS1. Furthermore, CD63 induces STAT3 activation to maintain the phenotype and function of CD63 + CAFs. Most importantly, the pharmacological blockade of CD63 + CAFs with a CD63‐neutralizing antibody or cRGD‐miR‐22‐sponge nanoparticles enhances the therapeutic effect of tamoxifen in breast cancer. In summary, the study reveals a novel subset of CD63 + CAFs that induces tamoxifen resistance in breast cancer via exosomal miR‐22, suggesting that CD63 + CAFs may be a novel therapeutic target to enhance tamoxifen sensitivity.

Na؉ /K ؉ -ATPase, a plasma membrane protein abundantly expressed in epithelial tissues, has been identified and linked to numerous biological events, including ion transport and reabsorption. In Na ؉ /K ؉ -ATPase, the ␤-subunit plays a fundamental role in the structural integrity and functional maturation of holoenzyme. Estrogens are important circulating hormones that can regulate Na ؉ /K ؉ -ATPase abundance and activity; however, the specific molecules participating in this process are largely unknown. Here, we characterize that N-myc downstream-regulated gene 2 (NDRG2) is an estrogen up-regulated gene. 17␤-Estradiol binds with estrogen receptor ␤ but not estrogen receptor ␣ to up-regulate NDRG2 expression via transcriptional activation. We also find that NDRG2 interacts with the ␤1-subunit of Na ؉ /K ؉ -ATPase and stabilizes the ␤1-subunit by inhibiting its ubiquitination and degradation. NDRG2-induced prolongation of the ␤1-subunit protein half-life is accompanied by a similar increase in Na ؉ /K ؉ -ATPase-mediated Na ؉ transport and Na ؉ current in epithelial cells. In addition, NDRG2 silencing largely attenuates the accumulation of ␤1-subunit regulated by 17␤-estradiol. Our results demonstrate that estrogen/NDRG2/Na ؉ /K ؉ -ATPase ␤1 pathway is important in promoting Na ؉ /K ؉ -ATPase activity and suggest this novel pathway might have substantial roles in ion transport, fluid balance, and homeostasis. Na ϩ /K ϩ -ATPase, a plasma membrane ion pump, has numerous physiological functions. Of note, it is consisted of three subunits (1), ␣, ␤, and ␥, and the holoenzyme activity required by the participation of the three subunits. ␣ is the catalytic subunit of the enzyme that utilizes ATP hydrolysis to pump K ϩ into the cell in exchange for Na ϩ , which is essential for maintaining normal resting membrane potentials and facilitating the exchange of other materials needed for cellular homeostasis and activity (2-4). ␤-Subunit is responsible for the formation and integrity of the holoenzyme. In vertebrate cells, ␤-subunit may stabilize the correct folding of the ␣-subunit to facilitate its delivery to the plasma membrane (5-7). In addition, evidence showed that ␤-subunit is related to the cell motility and invasion (8, 9). At present, four ␣-isoforms known as ␣1, ␣2, ␣3, ␣4 as well as three different ␤-polypeptides termed as ␤1, ␤2, and ␤3 (3) have been identified. Among these isoforms, ␣1␤1 distributes in nearly every tissue whereas other isoforms exhibit a tissue-specific pattern of expression. ␥-Subunit, a small hydrophobic polypeptide that has only one isoform, is involved in the modulation of Na ϩ /K ϩ -ATPase function (10, 11). The ionic homeostasis maintained by the Na ϩ /K ϩ -ATPase is also critical for cell survival, differentiation, and cell apoptosis (12, 13).As an important molecule in charge of so many biological events, Na ϩ /K ϩ -ATPase is regulated by a number of hormones, including aldosterone, thyroid hormone, glucocorticoid, catecholamines, insulin, carbachol, and androgen. These circulating horm...

HOXD10, a key regulator of cell-differentiated phenotype maintainence, has been demonstrated to be involved in the tumorigenesis of many human malignacies. However, the status of HOXD10 expression and its biological function in cholangiocellular carcinoma (CCC) remain to be clarified. In the present study, we investigated the clinical significance and biological functions of HOXD10 in CCC and found that the expression of HOXD10 and its downstream effector RHOC was significantly different in well-differentiated CCC tissues compared with poorly-differentiated lesions. We also observed a significant correlation between low HOXD10 and high RHOC expression levels and worse prognosis. The stable overexpression of HOXD10 by lentivirus vector significantly inhibited cell invasion partly by downregulating the expression of MMP2 and MMP9, and significantly increased early apoptosis in CCC cell lines and induced G1 phase cell cycle arrest, contributing to the inhibition of cell proliferation in vitro. Additionally, we demonstrated that the inactivation of the RHOC/AKT/MAPK pathway was involved in the tumor-suppressive functions of HOXD10 in CCC. These results suggested that HOXD10 may be a putative suppressor gene and can act as a prognostic marker and potentially a novel therapeutic target for CCC.

Background: NDRG2 (N-Myc downstream-regulated gene 2) was initially cloned in our laboratory. Previous results have shown that NDRG2 expressed differentially in normal and cancer tissues. Specifically, NDRG2 mRNA was downregulated or undetectable in several human cancers, and over-expression of NDRG2 inhibited the proliferation of cancer cells. NDRG2 also exerts important functions in cell differentiation and tumor suppression. However, it remains unclear whether NDRG2 participates in carcinogenesis of the thyroid.