over the past decade , the emergence of mirna research has firmly established this molecular family as a key component in cells . under normal physiological conditions , mirnas implement feedback mechanisms by gene transcripts to regulate cell proliferation , differentiation and apoptosis 1 - 3 . the dysregulation of mirnas may facilitate malignant transformation , including tumor initiation , growth , invasion , and therapeutic resistance 1 - 3 . recently , several investigations have reported that mir-196 is frequently altered in various cancers , which suggests that it plays an important role in carcinogenesis . here , we review recent reports on mir-196 family molecules in cancer , whose topics include gene structure , biological functions , and regulatory targets and clinical significance . we highlight that mir-196 may serve as an emerging cancer biomarker for digestive tract cancers . mirnas are endogenous , non - coding small rna that are approximately 22 nt in length . after the first mirna was discovered in c. elegans , in 1993 , the knowledge of mirna grew rapidly 1 . currently , more than 2,500 potential human mirnas are recorded in the mirbase , and more than 30% of all genes are estimated to be regulated by mirnas . this family of molecules has important and broad functions in cells , including proliferation , differentiation and apoptosis 2 - 6 . their long primary transcripts are produced by rna polymerase ii and are further processed by drosha and dgcr8 , which results in 80- to 100-nt precursor mirnas ( pre - mirnas ) 7 , 8 . the pre - mirnas are transported to the cytoplasm by expotin5 and are cleaved by dicer to form double - stranded mirna duplexes . after unwinding into single - stranded mature mirnas , the mirnas bind to argonaute ( ago2 ) protein and form this complex then binds to the target - gene mrna , and carries out mrna degradation or translational repression 2 , 9 . more specifically , the mature mirna recognizes its complementary sequence in the target mrna 3'-untranslational region ( 3'-utr ) via the  seed  region of the 5'-mirna at nucleotide positions 2 - 7 . recent reports have revealed that the target mrnas may also be repressed by mirnas through binding to the coding regions or 5'-utr 10 , 11 . mirnas play as negative gene regulators in cells and function based on their target transcripts . through algorithm analysis of mirna target prediction , plenty of mirna - gene relationships increasing evidences have shown that a single mirna is able to regulate several transcripts , and a transcript may have multiple mirna binding sites which allow several mirnas to bind at a same time 14 . the dysregulation of mirna may contribute to numerous disorders , including cancer , immune - related and neurodegenerative diseases 15 . mirnas are frequently found located at the genomic fragile sites or the oncogenic associated regions , which suggests that mirna molecules participate in malignant transformation 16 , 17 . accumulating studies have demonstrated that mirnas can serve as either tumor suppressors or oncogenes 18 - 20 . there are three mir-196 genes in human cells : mir-196a-1 , mir-196a-2 , and mir-196b . they are all located in the hox gene clusters and produce two mature mirna family members : mir-196a and mir-196b 21 . the mir-196a-1 and mir-196a-2 genes are located on chromosomes 17 and 12 , respectively 22 . both of these genes transcribe the same mature mir-196a molecule , which has the sequence 5'-uaggua- guuuca- uguugu- uggg-3 ' . the mir-196b gene is located on chromosome 7 and transcribes a mature mir-196b molecule with the sequence 5'-uaggua- guuucc- uguugu- uggg-3 ' 23 . there is only one nucleotide difference between mature mir-196a and mir-196b , though both possess the same seed region . although high similarity exists between mir-196a and mir-196b , these two molecules have a wide range of expression and diverse roles in various types of cancers . for example , mir-196a has been reported to be over - expressed in head - neck 24 , oral 25 , 26 , gastric 27 , 28 , pancreatic 29 , 30 , cervical 31 , 32 , and lung 33 cancers . similarly , mir-196b has been found to be up - regulated in the cancers of oral 25 , gastric 34 , colorectal 35 , 36 , as well as in glioblastoma 37 and in leukemia 23 , 38 . the functions of the oncogenic effects of mir-196 family molecules include promoting cell proliferation , migration , invasion and radioresistance 21 - 34 . however , few reports have indicated that the mir-196 family may act as tumor suppressors . for example , mir-196a suppresses metastasis in melanoma 39 and breast cancers 40 , and mir-196b is down - regulated in different types of leukemia cells 41 , 42 . collectively , both mir-196a and mir-196b are frequent aberrations in malignant diseases , and which indicates their close association with disease status . because mirnas function as gene regulators , identifying mirna targets allows delineation of the specific function of a mirna . several computational software packages have been developed to predict potential mirna targets by aligning the conserved seed region of a mirna to the complementary sequences on the 3'-utr region of a mrna 43 . table 2 summarizes the expression , target genes , and functions of mir-196 family molecules in diverse cancers . the oncogenic functions of these molecules have been found to target diverse tumor suppressors in specific types of cancer tissues . for example , in oral cancer , both mir-196a and mir-196b down - regulate the expression of metastasis suppressor nme4 to accelerate cell migration and invasion 25 . in esophageal and head - neck cancers , mir-196a targets annexin a1 to promote cell growth , mobility and radioresistance 24 , 44 . in gastric cancer , mir-196a down - regulates p27 , a cell cycle g1 check - point regulator , to promote cell proliferation 27 . also in gastric cancer , both mir-196a and mir-196b promote cell metastasis via suppression of radixin 45 . in pancreatic cancer , mir-196a restrict the expression of hoxa7 , hoxb8 , hoxc8 and hoxd8 genes , leading to the activation of the akt pathway and increase cell mobility 46 . a high level of mir-196b in colorectal cancer also repressed fas expression to modulate cell apoptosis 36 . in cervical cancer , mir-196a inhibits p27 , foxo1 or netrin 4 to facilitate cell proliferation or migration 31 , 32 . nevertheless , few studies have reported on the function of the mir-196 family as a tumor suppressor by targeting oncogenes . for example , in melanoma and breast cancer , mir-196a suppresses hoxc8 , a transcription factor , to inhibit cell growth , invasion and metastasis 47 , 48 . in chronic myeloid leukemia , mir-196b is down - regulated in cells and enhances the functions of oncogenes bcr - abl1 and hoxa9 41 . aside from the mirna - downstream target gene axis , the upstream regulatory mechanism of mir-196 has also been reported , mainly through epigenetic associated mechanism 49 . the cpg islands in the mir-196b promoter showed more methylation in chronic myeloid leukemia patients than healthy individuals 41 . in gastric cancer , mir-196b has been found regulated by est2 through an epigenetic pathway 50 , 51 . furthermore , mir-196a2 gene possesses single nucleotide polymorphism in many cancers , including in breast , head - neck , lung and oral cancers , which may result to target binding deficit and increasing cancer susceptibility 26 , 52 - 58 . taking together , mir-196 family molecules play important roles in homeostasis , and dysregulation of this family closely associated with various malignancy . although vary in level , mir-196 family molecules are consistently found over - expressed in digestive tract cancer tissues , which comprise of mouth , esophagus , stomach , small intestine , and large intestine . table 3 summarizes the clinicopathological association of mir-196 family molecules in digestive tract cancers . on the differentiation of normal and cancer tissues , both mir-196a and mir-196b are significantly elevated in oral cancer tissues compared to the adjacent normal counterparts 25 , indicating that mir-196 may be a putative diagnostic marker . consistently , mir-196a is up - regulated in laryngeal cancer and able to discriminate normal and cancer tissues 59 . in esophagus , mir-196a shows correlative expression during cancer progression , as gradually higher from normal tissue , metaplasia , dysplasia , to invasive adenocarcinoma 60 . in addition to the diagnostic potential , mir-196 family molecules have also been reported associated with clinicopathological status of the digestive tract cancers , which implies the potential in using of these molecules in prognostic application . for examples , both mir-196a and mir-196b are up - regulated in oral cancer tissues and associated with lymph node metastasis 25 . the high level of mir-196a in head - neck cancer tissue also contributes to radioresistance 24 . in gastric cancer , mir-196a or mir-196b is linked to advanced pathologic stage , cancer recurrence and shorter survival 27 , 34 , 45 , 61 . concordantly , both mir-196a and mir-196b in colorectal cancer shows cooperatively correlated with aggressive disease and unfavorable to treatment outcome 35 . taken together , mir196 family molecules in digestive tract cancers may serve as biomarkers for clinical applications in diagnosis , prognosis , or prediction of treatment efficacy . detecting biomolecules in body fluids , including peripheral blood , urine or saliva , provides a less invasive process to facilitate clinical applications . recently , many reports have revealed that mirnas can be exosomic released from tumor cells , stably expressed in circulation , which may be suitable to be utilized as promising biomarkers 62 - 65 . regarding mir-196 family , several studies have shown that mir-196 molecules are detectable in the peripheral blood from digestive tract cancer patients and associated with clinical significance . for example , mir-196a and mir-196b are significantly elevated in the sera of patients with chronic pancreatitis or pancreatic cancer compared to those from normal individuals 66 , 67 . concordantly , the combined determination of mir-196a and mir-196b produces high sensitivity and specificity for the early detection of pre - malignant or malignant oral diseases 68 . circulating mir-196a also showed high potential to be a prognostic marker because it correlated with patient survival in recurrence status of gastric cancer 28 or in pancreatic cancer 67 . as stated above , mir-196 is elevated in the blood of patients with several types of digestive tract cancers . however , these results were obtained from various investigators who used different assay protocols which may lead to possible bias . to assess the diagnostic potential , we compared the mir-196b level in the plasma from healthy individuals and from patients with several types of cancers , including nasopharyngeal , oral , esophageal , gastric , colorectal and lung cancers . mir-196b was substantial increased in digestive tract cancer patients , with an average elevation of 3.7- to 25.6-fold ( p < 0.001 for all ) . the detection power of mir-196b for each cancer is summarized in table 4 ( youden index 69 ) . such high ability to discriminate between healthy individuals and cancer patients indicates that mir-196b may serve as a powerful circulating tumor marker for the detection of digestive tract cancers . detecting biomolecules in body fluids , including peripheral blood , urine or saliva , provides a less invasive process to facilitate clinical applications . recently , many reports have revealed that mirnas can be exosomic released from tumor cells , stably expressed in circulation , which may be suitable to be utilized as promising biomarkers 62 - 65 . regarding mir-196 family , several studies have shown that mir-196 molecules are detectable in the peripheral blood from digestive tract cancer patients and associated with clinical significance . for example , mir-196a and mir-196b are significantly elevated in the sera of patients with chronic pancreatitis or pancreatic cancer compared to those from normal individuals 66 , 67 . concordantly , the combined determination of mir-196a and mir-196b produces high sensitivity and specificity for the early detection of pre - malignant or malignant oral diseases 68 . circulating mir-196a also showed high potential to be a prognostic marker because it correlated with patient survival in recurrence status of gastric cancer 28 or in pancreatic cancer 67 . as stated above , mir-196 is elevated in the blood of patients with several types of digestive tract cancers . however , these results were obtained from various investigators who used different assay protocols which may lead to possible bias . to assess the diagnostic potential , we compared the mir-196b level in the plasma from healthy individuals and from patients with several types of cancers , including nasopharyngeal , oral , esophageal , gastric , colorectal and lung cancers . mir-196b was substantial increased in digestive tract cancer patients , with an average elevation of 3.7- to 25.6-fold ( p < 0.001 for all ) . the detection power of mir-196b for each cancer is summarized in table 4 ( youden index 69 ) . such high ability to discriminate between healthy individuals and cancer patients indicates that mir-196b may serve as a powerful circulating tumor marker for the detection of digestive tract cancers . mir-196 offers a great potential as a biomarker for cancer detection , diagnosis , prognosis , and therapeutic assessment via both tumor tissues and circulating specimens . it will be imperative to carry out prospective trials in well - defined , large cohort studies to validate its clinical significance . determining the mir-196 level by using a minimally invasive method may be developed and applied in personalized cancer medicine .
over the past decade , the emergence of microrna ( mirna ) research has firmly established this molecular family as a key component in cells . 
 mirnas , which function as negative gene regulators , participate in multiple biological processes and maintain homeostasis in cells . 
 the dysregulation of mirna may contribute to numerous human disorders , including cancer . 
 recently , mir-196 was found to be aberrantly expressed in a wide range of malignant diseases , which suggests that it plays important roles in carcinogenesis . here , we summarize the current knowledge concerning mir-196 family in cancers . 
 this review includes mir-196 gene structure and aberrant expression in various cancers , and current understanding of numerous functions and regulatory targets of mir-196 in specific cancers . 
 since mir-196 are consistently found over - expressed in digestive tract cancer tissues , we also reviewed the clinical significance and potential applications of mir-196 in these cancers . 
 we highlight that mir-196 may serve as an emerging cancer biomarker for digestive tract cancers .