However, the inclination of CD44 expression inside these cells was remarkably completely contrary to that in exosomes . Epithelial-mesenchymal transition, Tumor initiation, Malignancy progression, Therapy-resistance, Targeted therapy Background Over the past decades, the conception that carcinoma represents a malignant disease type with both phenotypic and genetic heterogeneity has become completely accepted in the field of oncology. Although huge advancement has been achieved in exact management of this progressive disease [1C3], local invasion, distant metastasis and therapy resistance hinder survival improvement among tumor individuals. A flurry of study offers sprung up in order to Tmem14a throw light upon the underlying molecular mechanisms. Cluster of differentiation 44 (CD44) is definitely a complex transmembrane adhesion glycoprotein, and fundamentally associates with the pivotal component of the extracellular matrix (ECM) hyaluronic acid (HA) . CD44 expresses in a variety of cell types in humans, including embryonic stem cells, differentiated cells and cancer cells . Distinct alternative splicing during the transcription process produces two isoforms of CD44, including the standard isoform (CD44s) and CD44 variant isoforms (CD44v) . Numerous studies have reported that CD44 not only prominently participates in normal cellular functions during physiological processes [7, 8], but also plays pivotal functions in pathological processes, especially tumors . CD44 plays important roles in diverse physiological processes, such as organ development, diverse immune functions and haematopoiesis . CD44-mediating processes include T cell differentiation, branching morphogenesis, proliferation, adhesion and migration .?For instance, loss-of-function of CD44 in mice contributed to abnormalities in bone-marrow colonization  as well as in P62-mediated mitophagy inducer the migration of lymphocytes to lymph nodes or the thymus . As observed in pregnant mice, CD44-deletion impaired the preservation of lactation?post-partum?and accelerated uterine involution . In another study, CD44 depletion suppressed the proliferation of easy muscle cells in mice as comparison to wild-type controls . It has been evident that CD44 as a surface biomarker of cancer stem cells (CSCs) and a vital regulatory factor of epithelial-mesenchymal transition (EMT) program is usually involved in the regulation of tumor initiation and development [6, 15C17]. Aberrant expression of CD44 and dysregulation of CD44 contribute to tumor formation of multiple cancer entities, including lung cancer , hepatocellular carcinoma , ovarian cancer , glioma , papillary thyroid carcinoma , head and neck squamous cell carcinoma (HNSCC) , astrocytic gliomas  and oral squamous cell carcinoma (OSCC) . In hepatocellular carcinoma cells (HuH7) which originally express CD44s rather than CD44v, silence of CD44 gene impaired the potential of spheroid formation and enhanced sensitivity to sorafenib and 5-fluorouracil (5\FU), accompanied by amazing downregulation of CSC-related genes including CD133 and EpCAM . The 3 untranslated region of CD44, acting as a competing endogenous RNA to microRNA-34a, boosts the sensitivity of liver CSCs to natural kill cells-mediated cytotoxicity via regulating UL16 binding protein 2 . In addition, CD44 also exerts significant effects on caner invasion and metastasis of various tumor types , such as lung adenocarcinoma , breast malignancy [28C30], neuroblastoma , gastric cancer , esophageal squamous cell carcinoma (ESCC) , colorectal cancer [34C37], prostate cancer , nasopharyngeal carcinoma , endometrial cancer , clear cell renal P62-mediated mitophagy inducer cell (RCC) carcinoma , pancreatic cancer , meningioma  and ovarian cancer . As has been reported, the intracellular domain name (ICD) of CD44 interacting with RUNX2 to form a co-transcription factor drives the migration of prostate cancer cell line P62-mediated mitophagy inducer PC3 through upregulating the levels of metastasis-related genes, such as matrix metalloproteinase 9 (MMP9) and osteopontin . However, CD44 epithelial isoform has been found to be negatively correlated with lymphatic invasion and metastasis of colorectal cancer based on the statistical analysis of.